Jli J<y^ ^"^'^ 
            
         
            
        ' 3JJNUAL REPORT 
            
         
            
        ..^^ --— National Eye Institute 
            
         
            
        f\J^ioS October-'l, 1985 - September 30, 1986 
            
         
            
        /9<^G REPORT OF THE SCIENTIFIC DIRECTOR 
            
         
            
        Jin H. Kinoshita, Ph.D. 
            
         
            
        During this past year considerable restructuring of the 
            
        intramural program has taken place. The Laboratory of Vision 
            
        Research (LVR) has been divided into smaller working units. 
            
        During the course of years the LVR accumulated a number of 
            
        unrelated research groups making the Laboratory difficult to 
            
        manage. Creating smaller units of scientists with similar 
            
        interests strengthens the interaction and helps the head of 
            
        the Laboratory to be more responsive to the needs of his 
            
        group. Three additional laboratories, Laboratory of Retinal 
            
        Cell and Molecular Biology, Laboratory of Immunology and 
            
        Laboratory of Mechanisms of Ocular Diseases have been created. 
            
        These laboratories join the Clinical Branch, Laboratory of 
            
        Sensorimotor Research, Laboratory of Molecular and Develop- 
            
        mental Biology and Laboratory of Pathology to constitute the 
            
        seven branches of the NEI Intramural Program. We feel the re- 
            
        organization makes for a more efficient means of managing the 
            
        research activities on the Bethesda campus. 
            
         
            
        During the year significant progress has been achieved in 
            
        many research areas. To illustrate this point four studies 
            
        will be cited in this report even though there are several 
            
        other intramural studies which are equally impressive. 
            
         
            
        For a number of years Dr. Robert Nussenblatt, Dr. Igal 
            
        Gery and their associates have been developing experimental 
            
        animals models which simulate the inflammatory eye diseases 
            
        known as uveitis. The most promising approach was found to be 
            
        the injection of a purified retinal protein, identified as S 
            
        antigen, into Lewis rats, guinea pigs and monkeys. Animals 
            
        immunized with S antigen developed clinical anterior and 
            
        posterior uveitis which was confirmed by histology. The 
            
        monkey model closely resembled the disease found in posterior 
            
        uveitis patients. Additional experimental study suggested to 
            
        the group that T-cells were involved in this ocular inflam- 
            
        matory process. Since cyclosporine, a complex peptide 
            
        isolated from a certain fungus, was known to suppress T-cell 
            
        activity, the NEI scientists thought of the possibility that 
            
        cyclosporine may alleviate this inflammatory eye process. 
            
        Remarkably the cyclosporine treatment completely prevented the 
            
        S-antigen induced uveitis in animals. 
            
         
            
        The laboratory studies encouraged Dr. Nussenblatt to test 
            
        the effectiveness of cyclosporine in patients with various 
            
        types of uveitis. Preliminary studies suggested that patients 
            
         
            
        -2- 
            
         
            
        with the inflammatory disorder known as Behcet's disease were 
            
        particularly responsive to cyclosporine treatment in that the 
            
        inflammatory process was dramatically alleviated. These 
            
        findings served as the basis for a full-scale randomized 
            
        clinical trial of cyclosporine as a method of treatment of 
            
        Behcet's patients. Dr. Nussenblatt arranged to have this 
            
        trial conducted as a multi-center study in Japan where there 
            
        is greater prevalence of these Behcet's cases than in this 
            
        country. This study was concluded recently and positive 
            
        results were obtained indicating that cyclosporine is indeed 
            
        effective against this form of uveitis. Thus, the series of 
            
        studies which began in the laboratory has led to the 
            
        development of a treatment of an inflammatory eye disease 
            
        where no specific treatment was known before. 
            
         
            
        For his contributions for the development of cyclosporine 
            
        as a therapeutic agent of uveitis Dr. Robert Nussenblatt will 
            
        be honored by the Japanese Ophthalmological Society in 1987. 
            
         
            
        Dr. Piatigorsky and associates of the LMDB have been 
            
        developing transgenic mice which have been used in an exciting 
            
        study that potentially has clinical relevance. These mice 
            
        permit the analysis of DNA sequences which are responsible for 
            
        the expression, tissue-specificity and developmental program 
            
        of gene expression. In their investigations they identified 
            
        numerous putative regulatory regions of the genes for a 
            
        specific lens protein, the a A-crystallin. Furthermore, 
            
        transient expression experiments using explanted lens 
            
        epithelia have provided evidence that these DNA sequences are 
            
        indeed responsible for the tissue-specific expression of the 
            
        crystallin genes. Recently, they created a DNA containing 
            
        .the a A-crystallin gene promoter (only 364 nucleotides) fused 
            
        with the bacterial chloramphenicol acetyltransferase gene 
            
        (CAT) . They injected this recombinant DNA into the nucleus of 
            
        a fertilized mouse egg and produced a male transgenic mouse 
            
        which had CAT activity in its ocular lens and only in the 
            
        lens. None of the 9 other tissues examined contained CAT 
            
        activity. This clearly permits further analysis of the 
            
        molecular nature of tissue-specific crystallin gene expression 
            
        at the level of the whole organism. Moreover, it kindles hope 
            
        for eventual gene therapy of ocular diseases. 
            
         
            
        For his many important contributions of the application of 
            
        molecular biology to the eye. Dr. Piatigorsky was the recip- 
            
        ient of the 1986 Friedenwald Award, one of the prestigious 
            
        awards presented by the Association for Research in Vision and 
            
        Ophthalmology . 
            
         
            
        Major advances in the study of gyrate atrophy have been 
            
        made by a team of scientists led by Dr. Muriel Kaiser-Kupfer. 
            
        Gyrate atrophy is a rare hereditary disease which leads to the 
            
        degeneration of the retina and choroid. This team of 
            
        scientists has shown that this disorder is caused by a 
            
        deficiency of the enzyme ornithine aminotransferase (OAT) 
            
         
            
        -3- 
            
         
            
        which results in a hyperornithinia in these patients. Dr. 
            
        Kaiser-Kupf er has shown that diets which restrict the sources 
            
        of ornithine seem to protect and even improve visual function. 
            
         
            
        Stimulated by these clinical studies, Dr. George Inana and 
            
        his colleagues began examining the gyrate atrophy problem 
            
        using DNA technology. They have been successful in isolating 
            
        a cDNA clone for human OAT. With this probe they are studying 
            
        the nature of the OAT gene defect in gyrate atrophy patients. 
            
        This study is an example of how rapidly a clinical problem can 
            
        be attacked with the most modern of research tools because of 
            
        the unique setting of the intramural program which fosters the 
            
        interactions of scientists from many disciplines. 
            
         
            
        For the development of the first cDNA probe to study an 
            
        ocular disease Dr. George Inana was honored as the principal 
            
        guest lecturer at the Proceedings of the Japanese Chapter of 
            
        the International Society of Eye Research in Sendai, Japan in 
            
        1985. 
            
         
            
        Dr. Wurtz has pioneered studies on the understanding of 
            
        how the brain uses visual information to produce eye 
            
        movements. His recent work, using old world monkeys as a 
            
        model system, has had two facets. First, he has extended his 
            
        analyses of the brain circuits that produce the rapid or 
            
        saccadic eye movements that move the eye quickly from one part 
            
        of the visual field to another. His studies were the first to 
            
        recognize that the basal ganglia of the brain participated in 
            
        controlling saccadic eye movements. The basal ganglia produce 
            
        a tonic inhibition on the saccadic control system of the 
            
        brainstem, the superior colliculus. In addition his recent 
            
        findings revealed that the neuronal transmitter is likely to 
            
        be GABA since he has been able to inhibit or facilitate eye 
            
        movements by injecting minute quantities of GABA agonists or 
            
        antagonists into the terminal area of basal ganglia fibers in 
            
        the superior colliculus. Thus, a major new control system 
            
        acting on the initiation of saccadic eye movements has been 
            
        revealed. His second series of experiments has been on a 
            
        second type of eye movement, the pursuit eye movements that 
            
        allow the eye to track moving targets. Dr. Wurtz 's group has 
            
        shown that these movements are normally dependent for their 
            
        visual input on a tiny area of cerebral cortex that is devoted 
            
        to processing of visual motion information. Furthermore, 
            
        minute damage produced by microliter injections of a 
            
        neurotoxic chemical into adjacent regions produces the 
            
        directional deficit in pursuit eye movements seen in human 
            
        patients with cerebral damage. These experiments show for the 
            
        first time the precise localization and function of the 
            
        cerebral cortical areas upon which pursuit eye movements are 
            
        dependent. 
            
         
            
        For these accomplishments Dr. Wurtz was honored by the 
            
        European Neuroscience Association which has designated him to 
            
        present the Gordon Holmes Lecture at the meeting of the 
            
        Association in September, 1985. 
            
         
            
        -4- 
            
         
            
        Although the intramural program faces difficult times 
            
        ahead because of restrictions in budget, personnel and space 
            
        it is encouraging that accomplishments like those cited here 
            
        can be achieved. This is a tribute to the intramural 
            
        scientists with their talents and enthusiasm who devote their 
            
        lives to dispel our ignorance in many problems related to the 
            
        eye . 
            
         
            
        PROJECT NUMBER 
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
         
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        ZOl EY 00065-09 DSD 
            
         
            
        '6c?S^ir^Y? 1985 to September 30, 1986 
            
         
            
        TITLE OP PROJECT ^80 cf>iracl»r$ or l»ss Titit must III or one Imt between me tmrOers ) 
            
         
            
        Physiological Studies of the Primate Visual System 
            
         
            
        PRINCIPAL INVESTIGATOR fUsf omei prolessKyte: penonne Oeio» tfte Prinapa' Inresiigeior j (Name tnle Wxyatoy eno insmurt aliimtion) 
            
         
            
        PI: Francisco de Monasterio M.D., Sc.D Medical Officer DSD, NET 
            
        Others:. Edna P, McCrane B.S. Biologist OSD, NEI 
            
         
            
        COOPERATING UNITS (if anyi 
            
         
            
        Howe Laboratory, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 
            
        Boston, Massachusetts. 
            
         
            
        LAB.'BRANCM 
            
         
            
        Office of the Scientific Director 
            
         
            
        SECTION 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        0.90 
            
         
            
        PROFESSIONAL OTHER 
            
         
            
        0.40 \ n.'in 
            
         
            
        CHECK APPROPRIATE BOXlESi 
            
         
            
        G (a) Human subjects D (b) Human tissues 51 (c) Neither 
            
         
            
        G (a1) Minors 
            
        G (a2) Interviews 
            
         
            
        SUMMARY OF WORK (Use stanaard unreaucea lype Dc not etceea tt>e space provioed ) 
            
         
            
        This project involves the study of the physiological organization of neurons of 
            
        the visual system of primates. We have examined the functional mapping on the 
            
        striate cortex of the innervation density mediated by the two major classes of 
            
        ganglion cells that respectively project to the parvocellular and magnocellular 
            
        layers of the lateral geniculate nucleus. We have found that the mannif fcation 
            
        in striate cortex is proportional to the afferent density of one cell type, and 
            
        that the so-called point-image area of striate cortex follows the reciprocal of 
            
        the afferent density of the other cell type. These differences between neural 
            
        maps are likely to have psychophysical consequences. In addition, an electro- 
            
        physiological survey of the variation of receptive-field size with eccentricity 
            
        is in progress, and we have begun preliminary recordings in striate and extra- 
            
        striate cortex to examine chromatic cell properties. Finallv, we are completing 
            
        analyses of previous studies for their publication. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl n 00135-lA OSD 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        FITlE of PROJECT (BC chvwcnri ex Itsi TiOt must tr or. on* lint t»rw»»r. ttte boroerz ) 
            
         
            
        Biochemistry of Retina and Pigmented Epithelium in Health and Disease 
            
         
            
        PRINCIPAL INVESTIGATOR (Lai otrm' pnttsiionti ptrtonnt. Cwtow the Pnnc<M' Inrtiligato' ) (Name. tme. labormlor, ana rtsorjit afl^^oon) 
            
        PI: Helen H. Hess M.D. Medical Officer (Research) OSD, NEI 
            
         
            
        COOPERATING UNITS (0 any) 
            
         
            
        Veterinary Resources Branch, DRS, NIH 
            
         
            
        AB/B RANCH 
            
         
            
        Office of the Scientific Director, ^fEI 
            
         
            
        JECTION 
            
         
            
        nstitltte and location 
            
         
            
        National Eye Institute, NIH, Bethesda, Maryland 20892 
            
         
            
        OTAL MAN-VEARS 
            
         
            
        1.4 
            
         
            
        PROFESSIONAL 
            
        1.0 
            
         
            
        OTHER 
            
        0.4 
            
         
            
        JHECK APPROPRIATE BOXfES) 
            
         
            
        3 (a) Human subjects 
            
        C (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues B (c) Neither 
            
         
            
        (UMMARy of work (Ute ttanaa'O unrwiuceO type Do not »tc»»<J tfte ifwce provioea ) 
            
         
            
        The effects of nutrition, oxidation, and other environmental factors 
            
        (light intensity or darkness) on the incidence and progress of 
            
        posterior subcapsular opacities (PSO) associated with retinal 
            
        degeneration are being studied in Royal College of Surgeons (RCS) 
            
        rats, in which rod photoreceptor outer segment debris accumulates 
            
        secondary to a phagocytic defect in the retinal pigmented epithelium. 
            
        Evidence has been obtained that oxidative changes in polyunsaturated 
            
        fatty acids in the debris lead to water-soluble toxic aldehydes that 
            
        can be detected in the vitreous, and are toxic to lens membranes. 
            
        Several diets have been found to prevent mature cataracts, and dark- 
            
        rearing has been shown to prevent the PSO detectable microscopically. 
            
        By exposing pink-eyed dystrophic rats to constant light of 25 
            
        footcandles beginning (1) at 20-23 postnatal days or (2) at birth, we 
            
        have been able for the first time to demonstrate histopathological 
            
        changes similar to those in some naturally occurring human posterior 
            
        subcapsular cataracts (PSC), such as those seen in retinitis 
            
        pigmentosa. Lens epithelial cells migrated to the posterior pole of 
            
        the lens. Many were bizarre in shape, with abundant pale-staining 
            
        cytoplasm and small (or large) nuclei ("bladder cells of Wedl"). 
            
        Changes similar to human anterior subcapsular cataracts were also 
            
        noted. RCS rats provide a readily manipulated animal model of PSC, 
            
        exacerbated by some environmental factors and prevented by others. 
            
        Principles established with the model may have significance for 
            
        slowing or preventing human PSC. 
            
         
            
        ANNUAL REPORT 
            
         
            
        NATIONAL EYE INSTITUTE 
            
         
            
        October 1, 1984 - September 30, 1986 
            
         
            
        REPORT OF THE DEPUTY CLINICAL DIRECTOR 
            
        Robert B. Nussenblatt, M.D. 
            
         
            
        The Clinical Branch consists of three Sections, each with its own Section 
            
        Head: Section on Ophthalmic Genetics and Pediatric Ophthalmology, Muriel I. 
            
        Kaiser-Kupfer, M.D.; Section on Neuro-ophthalmology, James Carl, M.D.; and the 
            
        Section on Retinal and Vitreal Diseases, Robert B. Nussenblatt, M.D. (Acting). 
            
         
            
        The Section on Ophthalmic Genetics and Pediatric Ophthalmology continues 
            
        its long-term interest in gyrate atrophy. Patients placed on a low arginine, 
            
        low protein diet with supplemental amino acids continue to be observed. The 
            
        group has also been actively pursuing better ways to control the deposition of 
            
        cystine crystal in the cornea of patients with cyctinosis. Patients with this 
            
        recessively inherited storage disease will accumulate nonprotein cystine 
            
        within cellular lyposomes . The ocular manifestations of this disorder include 
            
        photophobia, crystal deposition in the cornea, conjunctiva, iris, and 
            
        depigmentation of the retina. A masked randomized clinical trial using 
            
        topical cysteamine has begun, in order to answer the question of whether this 
            
        approach will prevent further deposition of crystals in the corneas of 
            
        cystinosis patients. Another important area of research includes the 
            
        documentation and monitoring of opacities in the human lens, of great import 
            
        with the potential availability of medications that may be of use in treating 
            
        cataract formation. 
            
         
            
        The Section on Retinal Diseases and Vitreous remains heavily involved with 
            
        two long term clinical trials. Sorbinil, an aldose reductase inhibitor given 
            
        orally, is being tested in a randomized masked study to see if it will inhibit 
            
        the development of diabetic retinopathy. Additionally, patients with senile 
            
        macular degeneration continued to be studied in this randomized masked study 
            
        in order to test the efficacy of vitamin E and C therapy as well as the 
            
        prevention of damage from light below 500 nanometers in preventing this 
            
        degenerative process, the leading cause of newly registered blindness in the 
            
        white adult population in the United States. The results of these two most 
            
        important trials will not be available for some time to come. In addition, 
            
        this group has studied the amount of flourescein leakage into the vitreous of 
            
        diabetic patients, using the vitreous f luorophotometer . Diabetic patients 
            
        with no microaneurysms have not demonstrated greater posterior vitreous 
            
        leakage as compared to controls. However, differences in vitreal leakage can 
            
        be noted in diabetic patients with minimal background retinopathy when 
            
        compared to controls. 
            
         
            
        The Neuro-ophthalmic Section has concentrated its efforts in two major 
            
        areas. They have devoted their efforts at developing methods for the analysis 
            
        of oculomotor disorders in human subjects. This has led to a computerized 
            
        facility which can stimulate an eye muscie weakness in normals using optical 
            
        means studies on congenital nystagmous which have shown that these patients 
            
         
            
        with an abnormality of their vestibulo-ocular reflex, and that some may use 
            
        this poor response to help them improve acuity by head shaking. Clonazepam 
            
        has been seen to quiet a variety of types of nystagmus. 
            
         
            
        The Clinical Branch reflects new horizons with basic research observations 
            
        playing an increasingly greater role in the research being conducted. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00213-01 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJEC (BO chB'actt'% O' *ss Jdie muj.' tit on one line tierwee'- rne boraers ) 
            
         
            
        Sensory and oculomotor contributions to ocular disorder 
            
         
            
        PRINCIPAL INVESTIGATOR (List or'rer profemont: pe'tonnel belo* rhe Pnncipa' InvesligaiO' ) (Name lilie laboratory, ana mstnule tKihauon 
            
         
            
        PI: Kent E. Higgins Ph.D. Expert CB, NEI 
            
         
            
        Others: Rafael C. Caruso M.D. 
            
        Edmond Thall M.D. 
            
         
            
        Monique S. Roy M.D. 
            
        Francisco de Monasterio M.D. 
            
        Robert Nussenblatt M.D. 
            
         
            
        Visiting Scientist CB, NEI 
            
         
            
        Staff Fellow CB, NEI 
            
         
            
        Visiting Scientist CB, NEI 
            
         
            
        Medical Officer OSD 
            
         
            
        Deputy Director CB, NEI 
            
         
            
        COOPERATING UNITS (i( any) 
            
         
            
        None 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Office of the Clinical Director 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
        1.97 
            
         
            
        PROFESSIONAL 
            
         
            
        1.07 
            
         
            
        OTHER 
            
         
            
        0.90 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        [?S (a) Human subjects 
            
        ^ (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        G (b) Human tissues 
            
         
            
        (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standard unreOucea type Do not exceed trie space provided ) 
            
         
            
        Spatial contrast sensitivity was used to assess losses or changes in overall 
            
        visual resolution in patients having a variety of toxic, inflammatory, 
            
        degenerative, or congenital retinal and neuro-ophthalmological disorders of 
            
        the visual system. A criterion-free forced-choice psychophysical procedure 
            
        was used, since this method was previously shown to minimize false positive or 
            
        false negative diagnoses at initial test and to minimize spurious changes in 
            
        sensitivity with repeated testing. Contrast sensitivity testing, while 
            
        requiring more patient testing time, continued to be superior to conventional 
            
        acuity measuremetns for the detection of early losses and for monitoring 
            
        changes in visual resolution in patients undergoing treatment. Age-referenced 
            
        normative data make it possible to distinguish contrast sensitivity loss due 
            
        to ocular disorder from that expected on the basis of normal aging. 
            
         
            
        A retinal image stabilization system was used in conjunction with the spatial 
            
        contrast sensitivity test system to carry our preliminary research on normal 
            
        subjects using artificial scotomata and complex spatial luminance profiles to 
            
        examine interactions among fixational errors, eye movements, and visual field 
            
        defects. This system is currently being modified to permit focal electro- 
            
        retinography and high resolution microperimetry in small, localized regions of 
            
        the retinas in Eye Clinic patients. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 002114-01 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 characnrz <y lets Tme musf ttr on one /me between me boraert I 
            
         
            
        Acquired and congenital color vision deficiencies: Mechanisms and diagnosis 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust oitter prulemonel personnel Oelow ir>e Pnncipei Investigiio' ) (Heme, me imboraiofy tno msmure eHiiiaiioni 
            
         
            
        PI: Kent E. Higgins Ph.D. Expert CB, NEI 
            
         
            
        Others: Kenneth B. Knoblauch Ph.D. 
            
         
            
        Edmond Thall M.D. 
            
         
            
        Francisco de Monasterio M.D. 
            
         
            
        Rafael C. Caruso M.D. 
            
         
            
        Robert Nussenblatt M.D. 
            
         
            
        Staff Fellow CB, NEI 
            
         
            
        Staff Fellow CB, NEI 
            
         
            
        Medical Officer CB, NEI 
            
         
            
        Visiting Scientist CB, NEI 
            
         
            
        Deputy Director CB, NEI 
            
         
            
        COOPERATING UNITS (it »ny) 
            
         
            
        None 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Office Of the Clinical Director 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, MD 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        1.2 
            
         
            
        PROFESSIONAL 
            
         
            
        1.1 
            
         
            
        OTHER 
            
         
            
        0.1 
            
         
            
        CHECK APPROPRIATE BOXlES) 
            
         
            
        E (a) Human subjects 
            
        C (al) Minors 
            
        C (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standanl unreduced type Do not exceed the space provided ) 
            
         
            
        This project involves the study of cone function in cases of color vision 
            
        defects, with special emphasis on the acquired color deficiencies. Human 
            
        subjects have been used for these studies which range from attempts to improve 
            
        quantification of data from existing standardized tests of color vision to the 
            
        collection of additional data for the purpose of designing better tests for 
            
        detecting color defects secondary to ocular disorder. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
         
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00117-06 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (80 chtrtcttn c l9Si Title must tit or one tine betwaer ffw txyOers ) 
            
         
            
        Oculomotor Disorders In Human Subject 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi otrter prolessionti parzonnei t»io» me Prmapai Inyesogator I (Name title lat>oratoy ano msiitjte afliiiation) 
            
         
            
        PI: James R. Carl M.D. Acting Head, Section on 
            
         
            
        Neuro-ophthalmology CB, NEI 
            
         
            
        Othersj Jon N. Currie F.R.A.C.P. Visiting Scientist CB, NEI 
            
        Victor Matsuo Ph.D. Senior Staff Fellow CB, NEI 
            
         
            
        COOPERATING UNITS (i> any) 
            
         
            
        Laboratory of Sensorimotor Research (R. Gellman, E. FitzGibbon, M. Goldberg); 
            
        Department of Neurology, Johns Hopkins Hospital (D. Zee). 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Neuro-Ophthalmology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        L^2. 
            
         
            
        ' PHOPESSIONAL ! OTHER 
            
         
            
        1.2 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        Gc (a) Human subjects D (b) Human tissues D (c) Neither 
            
         
            
        C (al) Minors 
            
        C (a2) Interviews 
            
         
            
        SUMMARY OF WORK (Use sianatra unreOuced type Do not exceed ttte space proviOed ) 
            
         
            
        The major emphasis of this project has been on developing methods for analyzing 
            
        oculomotor disorders in human subjects. Further development of the computerized 
            
        system for stimulus presentation and eye movement recording has enabled us to 
            
        present brief sets of visual tasks and collect data to evaluate each of the 
            
        ocular motor subsystems. Additional work on the analysis programs has increased 
            
        the sensitivity of these tests. 
            
         
            
        A second phase of the project has been to develop a detailed data base of normal 
            
        human responses to various stimuli. We have recently concentrated on smooth 
            
        pursuit eye movements, which have not previously been well characterized. 
            
         
            
        The computerized facility has allowed us to simulate an eye muscle weakness in 
            
        normal subjects by optical means, and we found that subjects were able to alter 
            
        the long latency pursuit response, but not the short latency one, to correct 
            
        for the simulated weakness. These tests have been applied to a few patients with 
            
        pursuit disorders and both short and long latency responses were abnormal. 
            
         
            
        Studies on congenital nystagmus were completed after finding that these patients 
            
        often have an abnormality of the vestlbulo-ocular reflex, and that some may use 
            
        this poor vestibular response to help them improve acuity by head shaking. 
            
        Other observations Included: benefit of clonazepam in quieting a variety of 
            
        types of nystagmus, continued analysis of horizontal saccadic abnormalities in 
            
        all types of Gaucher's disease, and development of abducting nystagmus in 
            
        multiple sclerosis patients as a result of adaptive changes after eye patching. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00160-C^ CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO charicleri or l»ss Tnit must In on oot lint b»tw»9n me exytit'i ) 
            
         
            
        Visual Inattention After Posterior Cerebral Hemisphere Lesions 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi of)*' proltsiiont! personnel below tt>e Pnncipai Investigator ) (Heme title laboratory ana msiniAt alliiiaiion) 
            
         
            
        PI: James R. Carl K.D. Acting Head, Section on 
            
         
            
        Neuro-ophthalmology CB, NEI 
            
         
            
        Others': 
            
         
            
        Jon N. Currle 
            
        Victor Matsuo 
            
         
            
        F.R.A.C.F. 
            
        Ph.D. 
            
         
            
        Visiting Scientist 
            
        Staff Fellow 
            
         
            
        CB, NEI 
            
        CB, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        Laborator>' of Sensory Motor Research, NEI (D.L. Robinson, S.E. Peterson, 
            
        M.E. Goldberg, E.J. FitzGibbon) 
            
         
            
        LAa'BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Neuro-ophthalmology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        .5 
            
         
            
        PROFESSIONAL 
            
         
            
        OTHER 
            
         
            
        CHECf APPROPRIATE BOXlESi 
            
         
            
        Gc (a) Human subjects 
            
        D (a1) Minors 
            
        C (a2) interviev^s 
            
         
            
        C (b) Human tissues G (c) Neither 
            
         
            
        SUMMAPv OF WORK (Use stanaara unraauced type Do not etceeO ttie space proviOea j 
            
         
            
        Attentional mechanisniF. important in visual behavior were studied in patients with 
            
        a variety of central nervous system abnormalities. 
            
         
            
        Shifts of visual attention as measured by reaction times were measured in 
            
        patients with parietal lobe damage, and compared to patients with frontal lobe 
            
        damage, Alzheimer's disease, or schizophrenia. 
            
         
            
        The patients with parietal lobe dysfunction demonstrated particular difficulty in 
            
        shifting attention away from the ipsilateral visual field, and this finding was a 
            
        reliable indicator of parietal cortical dysfunction. 
            
         
            
        Male patients with idiopathic hypogonadotrophlc hypogonadism also had abnormal 
            
        responses: they were slow in responding to targets in their right visual field. 
            
         
            
        Eye movements were evaluated in these patient groups, with pursuit movements and 
            
        fixational stability emphasized. In some patients, square wave jerks present 
            
        during fixation and reading were indications of attentional disorders. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (80 chartclers or less Tiitt must tit on one line between trie boroers I 
            
         
            
        Vitreous Fluorophotometry 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00162- OA CB 
            
         
            
        PRINCIPAL INVESTIGATOR (List otrte' prolessionai personnel beio* ttie Principal Investigator i (Name title laboratory ana mstitute affw-aron/ 
            
         
            
        PI: Monique Roy 
            
         
            
        M. D. 
            
         
            
        Visiting Scientist 
            
         
            
        CB, NEI 
            
         
            
        COOPERATING UNITS (il •nyj 
            
         
            
        None 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Retinal and Vitreal Diseases 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        1.50 
            
         
            
        PROFESSIONAL 
            
         
            
        1.50 
            
         
            
        OTHER 
            
         
            
        0.00 
            
         
            
        Check APPROPRIATE BOX(ESi 
            
         
            
        X (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        Summary of work /use stanaara unreduced type Do not exceed the space provided ) 
            
         
            
        Vitreous fluorophotometry has been performed in patients with diabetes 
            
        mellitus without retinopathy, patients with diabetes mellitus with 
            
        nonproliferative retinopathy, and normal volunteer subjects, age- and sex- 
            
        matched to the patients. The amount of fluorescein leakage into the vitreous 
            
        of patients has been compared to that of the normal subjects. Correlations 
            
        with other features of diabetes, such as the quality of diabetic control, the 
            
        existence of subclinical neuropathy and nephropathy, and others were sought. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 000198- 03 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 cftaracle's <y lea Tide muH lii or one line between the borOe's ) 
            
         
            
        Sorbinil Retinopathy Trial 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust otne' peoleiiionai pe'ionnei oeio* lt>e Principal Investigator j (Name title lat>oraiory. ana mslitute attiiiaiion) 
            
         
            
        PI: Monique Roy M. D. Visiting Scientist CB, NEI 
            
         
            
        Others': Manuel Datiles M. D. 
            
        James Carl M. D. 
            
         
            
        Staff Ophthalmologist CB, NEI 
            
        Senior Staff Fellow CB, NEI 
            
         
            
        COOPERATING UNITS (i' anyi 
            
         
            
        Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute 
            
        of Arthritis, Diabetes, and Digestive and Kidney Diseases, NIH (R. Silverman) 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Retinal and Vitreal Diseases 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        2.35 
            
         
            
        PROFESSIONAL 
            
         
            
        1.25 
            
         
            
        OTHER 
            
         
            
        1.1 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        K (a) Human subjects 
            
        D (a1) Minors 
            
        G (a2) Interviews 
            
         
            
        □ (b) Human tissues 
            
         
            
        D (c) Neither 
            
         
            
        SUMMARV OF WORK (Use slanaa'C unreauceO type Do not exceea the space proviOea ) 
            
         
            
        Oral sorbinil, an aldose reductase inhibitor, will be administered in a 
            
        double-masked randomized trial to diabetics with no or minimal diabetic 
            
        retinopathy. This will be done to evaluate the effects of sorbinil on the 
            
        development of diabetic retinopathy and further investigate the safety and 
            
        toleration of sorbinil. The study will be conducted simultaneously in 11 
            
        research centers in the USA. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY OO187-03-:e 
            
         
            
        PEPiOO COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO cht'iciert ot Itss Title must tit on one line between the bordeis j 
            
         
            
        The Effects of Corneal Contact Lenses on the Cornea 
            
         
            
        PRINCIPAL INVESTIGATOP (List olhe' proletsionti penonnei twtotv the Pimcipai Investigaloi ) (Heme, title. Itboflory. mno msMute ettiiiauon) 
            
         
            
        PI: Manuel B. Datiles M.D. Visiting Scientist CB, NEI 
            
         
            
        Others: Carl Kupfer M.D. 
            
         
            
        Lessie McCain R.N, 
            
         
            
        Muriel I. Kaiser-Kupf er M.D. 
            
         
            
        Director neI 
            
         
            
        Clinical Technician CB, NEI 
            
        Head, Section on CB, NEI 
            
         
            
        Ophthalmic Genetics 
            
        and Pediatric Ophthalmology 
            
         
            
        COOPERATING UNITS frf enf) 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and Pediatric Ophthalmology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN YEARS 
            
         
            
        .2 
            
         
            
        PROFESSIONAL 
            
        10 
            
         
            
        »fHER. 
            
        ^L 
            
         
            
        CHECK APPROPRIATE eOX(ES] 
            
         
            
        E (a) Human subjects 
            
        D (al) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues d (c) Neither 
            
         
            
        SUMMARY OF WORK (Use slenoard umeOuced type Do not exceed the space provided ) 
            
         
            
        Short- as well as long-term effects of contact lens wear on the cornea are being 
            
        Investigated. Changes in corneal curvature, changes in corneal epithelial 
            
        morphology and changes in corneal endothelial cell morphology are being studied 
            
        by specular microscopy. 
            
         
            
        These data will help us understand the dynamics involved in the interaction 
            
        between a contact lens and the cornea, the risk involved to corneal tissues, and 
            
        how a systemic or local disorder may increase these risks. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00138-03 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 chtrtcieri or fis Title must hi on oo* lint beiwatn the borOtrs ) 
            
         
            
        Documentation and Monitoring of Opacities in the Human Lens 
            
         
            
        PRINCIPAL INVESTIGATOR (Uit oif>t' prottssional personnti Cwtow lt>t Principal Invtstignor ) (Ntmt. title, labortlorf. ana mstitt/tt tflilitiion) 
            
         
            
        PI: Manuel B. Datiles M.D. Visiting Scientist CB, NEI 
            
         
            
        Others: Carl Kupfer M.D. 
            
         
            
        Robert Sperduto M.D. 
            
         
            
        Peter Kador Ph.D. 
            
         
            
        Lassie McCain R.N. 
            
         
            
        Director jjEI 
            
         
            
        Head, Epidemiology Branch BEP, NEI 
            
         
            
        Head, Section on LMOD, NEI 
            
         
            
        Molecular Pharmacology 
            
         
            
        Clinical Technician CB, NEI 
            
         
            
        COOPERATING UNITS (it tny) 
            
         
            
        Image Processing and Analysis Laboratory, DCRT, NIH (Benes Trus, Ph.D., Chief) 
            
         
            
        LAB'BRANCh 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and Pediatric Ophthalmology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN YEARS 
            
        .7 
            
         
            
        PROFESSIONAL 
            
        .5 
            
         
            
        OTHER 
            
        .2 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        K (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        Summary of work (use sianoara unreduced type Do not exceed the space provided ) 
            
         
            
        We are developing objective and subjective methods to monitor and document 
            
        opacities in the human lens using different systems. We are presently actively 
            
        recruiting patients with and without cataracts for reproducibility studies on 
            
        the objective systems--the Scheimpflug cameras (Zeiss and topcon), Retroillurai- 
            
        nation camera (Neitz), Specular microscope (Keeler) and laser light-scattering 
            
        spectroscope (KOWA). We will also test other systems using sound (ultrasono- 
            
        graphy), and nuclear magnetic resonance (magnetic resonance imaging). We are 
            
        also studying subjective systems or method, such as the effects of cataracts on 
            
        visual perception, contrast sensitivity, and glare, which may be useful as 
            
        additional parameters in the monitoring of cataract T)resence , progression, or 
            
        regression. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        7m rv nn?i?-ni ru 
            
         
            
        PERIOD COVERED 
            
         
            
        Of^tober 1 . ^9B'^ to 
            
         
            
        September ?n, IQfifi 
            
         
            
        TITlE OF PROJECT iBCi cht'tciea O' /ess Tut n.^n I,; or one Ime btrweer We bO'Oers ) 
            
         
            
        Model Program for Collaboratlnn Betw epn C.^^t.^rfirt t^iipgpnn.'^ and nphthalm<f Ro<;oa>>i->i^orc} 
            
         
            
        nuue-L rim}[ gill i ur ^^uj. j.auuf ai. i u ii nfri.wrrtrn uni.ni a\.i, niti ;^nwii.-i — mm — n)jiii.ii<-i i in i i.- i 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi oinar pto'tmont. personnti Oe/Oiv the Ptmcip*: lnvesl>ga!0' ) (Name. Mie. la:>oretO')\ ana mstiiate attii.ahon) 
            
         
            
        PI: Manuel B. Datiles 
            
         
            
        Othere: Carl Kupfer 
            
         
            
        Samuel Zigler 
            
         
            
        Peter Kador 
            
         
            
        M.D. 
            
         
            
        M.D. 
            
        Ph.D. 
            
         
            
        Ph.D. 
            
         
            
        Visiting Scientist 
            
         
            
        CB, NEI 
            
         
            
        Director NEI 
            
         
            
        Head, Section on LMOD, NEI 
            
         
            
        Cataracts 
            
        Head, Section on LMOD, NEI 
            
         
            
        Molecular Pharmacology 
            
         
            
        «=°9f6ft5iil^'^'nt^''*''''Uin H. Kinoshlta 
            
        George Inana 
            
         
            
        Ph.D. Scientific Director NEI 
            
        M.D., Ph.D Head, Section on LMOD, NEI 
            
        Molecular Pathology 
            
         
            
        LAB BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and P erliat-rip nphthalmnT ngy 
            
         
            
        INSTITUTE ANC LOCATION 
            
         
            
        NEI. NIH. Bethesda. Maryland PORQ? 
            
         
            
        TOTAL K'ANVEARS i pRQFESSONAl 
            
         
            
        OTHER 
            
         
            
        .*i5_ 
            
         
            
        .^s 
            
         
            
        CHECK APFROPRiATE BOX;ES) 
            
         
            
        2l (a) Human subjects G (b) Human tissues D (c) Neither 
            
        D (ai) M.nors 
            
        D (a2) Interviews 
            
         
            
        SUMMARY OF WORK (Uie stanaara unreojcei type Do no: exceed me space proviOec ) 
            
         
            
        There is presently an extreme dearth of human cataract material because of an 
            
        abrupt shift of cataract surgical technique from intracapsular (intact lens) 
            
        to extracapsular (fragmented lens), primarily because of advent of the use of 
            
        Intraocular lens. We are exploring ways by which fragmented lens materials 
            
        can be maximally used in cataract basic research through close collaboration 
            
        between cataract surgeons and basic researchers and modification of techniques 
            
        by both groups. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00011-12 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        nnl-nhPr 1, IQR'^ to .<:;ppt.Pmhpr ^0. 1Qfl6 
            
         
            
        TITLE OF PROJECT ^80 chvtctmrt oc Ksi TiO* mujf lit on Off knt b»Ni»*n tht borOtn ) 
            
         
            
        Pi gment ni.spprslnn With and Without Glaucoma 
            
         
            
        PRINCIPAL INVESTIGATOR (Ull Mhtr prjitistonti prtonntl b»>Ow tht PnnapaJ Invtstigilor ) {Hunt, OM. fborKor/. and niMurt ttlihtoon) 
            
         
            
        PI: 
            
         
            
        Muriel I. Kalser-Kupfer M.D, 
            
         
            
        Others: Carl Kupfer 
            
         
            
        Lessie McCain 
            
        Sandeep Jain 
            
         
            
        M.D. 
            
        R.N. 
            
         
            
        M.D. 
            
         
            
        Head, Section on Ophthalmic 
            
        Genetics and Pediatric 
            
        Ophthalmology 
            
         
            
        Director 
            
         
            
        Clinical Technician 
            
         
            
        Visiting Fellow 
            
         
            
        CB, NZI 
            
         
            
        NEI 
            
        C3, NEI 
            
         
            
        CB. NEI 
            
         
            
        COOPERATING UNITS (il tny) 
            
         
            
        LAaBRANCM 
            
         
            
        CA inlral Rrannh 
            
         
            
        SECTION 
            
         
            
        Spot Inn nn 
            
         
            
        Ophthalmln Qpnetifis and Ppriiatrin nphthalmnlngy 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NFT, NTH, RpthPsda , Maryland PORQ? 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        1.55 
            
         
            
        PROFESSIONAL 
            
         
            
        1.35 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE 80X(ES) 
            
         
            
        IS (a) Human subjects 
            
        D (al) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Uit slanaard unrwOuced type Do not BMceoO tt>e space providea ) 
            
         
            
        The purpose of this project is to compare patients with and without glaucoma 
            
        having pigment dispersion syndrome. The data acquired may enable a determina- 
            
        tion of the risk of patients with pigment dispersion syndrome to developing 
            
        glaucoma as well as add to understanding of the pathology of the the disease. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 0006?- in r.R 
            
         
            
        PERIOD COVERED 
            
         
            
        notnher 1. 1Q8S to September ^0. 1986 
            
         
            
        TITLE OF PROJECT (BO cfivcltrs a <•» TiO* must hi on on* knt batw—n tht OofOtn ) 
            
         
            
        Irido-Corneal-Endothellal (ICE) Syndrome 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust othf prottsuonal purtonnti bttomr tttm Pnnc^Ml Inviligtlor ) (Ntmm. titf. laborulofy. vx] mt/iutt ittiiittion) 
            
         
            
        PI: 
            
         
            
        Others: 
            
         
            
        Muriel I. Kaiser-Kupfer M.D. 
            
         
            
        Carl Kupfer 
            
        Lessie McCain 
            
        Manuel Datiles 
            
         
            
        M.D 
            
         
            
        R.N. 
            
         
            
        M.D. 
            
         
            
        Head, Section on Ophthalmic 
            
        Genetics and Pediatric 
            
        Ophthalmology 
            
         
            
        Director 
            
         
            
        Clinical Technician 
            
         
            
        Visiting Scientist 
            
         
            
        CB, NEI 
            
         
            
        NEI 
            
        CB, NEI 
            
         
            
        CB. NEI 
            
         
            
        COOPERATING UNITS (H tny) 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and Pediatric Ophtha''.ninlogy 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NET, NTH, Rpthesda, Maryland PORQ? 
            
         
            
        TOTAL MAN-YEARS. 
            
        . 3 S 
            
         
            
        PROFESSIONAL. 
            
         
            
        ^J2^ 
            
         
            
        OTHER 
            
         
            
        ..J. 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        CS (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Ui» sianaartl unrtducaO type Do not excsecJ ff)» space proviOea ) 
            
         
            
        This project was formerly titled "Progressive Essential Iris Atrophy." 
            
        Patients are being recruited with progressive essential iris atrophy with or 
            
        without associated corneal disease. Information is being gathered to evaluate 
            
        the clinical features and course of the disease process and to investigate 
            
        aqueous humor dynamics in both affected and unaffected eyes. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00083-09 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        nnt.ohpr 1, IQQS to 5;pptember ?0. 1986 
            
         
            
        TITLE OF PROJECT (BO chvtcfrt or Jan Tittt mutt lit on ont hot iMtw—n th» txyrytrt ) 
            
         
            
        r.yratp Atrophy of the Choroid and Retina 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust otf>»r pro/atsioffi perjonn*/ below ttit Principal Inyastigator ) (Stmt, titlt. Itborttoiy, tn<3 tMUtutt tlliimtton) 
            
         
            
        PI: Muriel I. Kalser-Kupfer M.D. Head, Section on Ophthalmic CB, NEI 
            
         
            
        Genetics and Pediatric 
            
        Ophthalmology 
            
         
            
        Oth^s: 
            
         
            
        Lessie McCain 
            
        Rafael Caruso 
            
        Kent Higglns 
            
         
            
        R.N. Clinical Technician 
            
        M.D. Visiting Scientist 
            
        Ph.D. Expert 
            
         
            
        CB, NEI 
            
        CB, NEI 
            
        CB, NEI 
            
         
            
        COOPERATING UNITS (t tny) 
            
         
            
        The Howard Hughes Medical Institute Laboratory and the Department of Pediatrics, 
            
        Johns Hopkins University, School of Medicine, Baltimore, Maryland 
            
        (David L. Valle. M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Bramch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and Pediatric Ophthalmologv 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 2Q892 
            
         
            
        TOTAL MAN YEARS 
            
         
            
        1.2 
            
         
            
        PROFESSIONAL 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(E$) 
            
         
            
        □ (a) Human subjects 
            
        C (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Uit sltnCtrd unnductd type Do not ttcfti tttt space pnjvidea j 
            
         
            
        Patients with gyrate atrophy of the choroid and retina are examined systematidal- 
            
        ly to confirm the diagnosis. Skin fibroblats of affected patients and family 
            
        members are grown in tissue culture and assayed for ornithine aminotransferase 
            
        activity. The results will be evaluated for correlation with the presence of 
            
        homo- or heterozygosity for the disease trait. Patients will be given a trial 
            
        of pyridoxlne to see if serum concentration of ornithine can be reduced, and, if 
            
        so, the patient will be classified as a "responder," and treatment with pyrido- 
            
        xlne will be continued. Nonresponder and responder patients will be placed on a 
            
        low arginlne, low protein, diet with supplemental amino acids and observed for an 
            
        arrest or Improvement of their disease. If patients are not considered eligible 
            
        for the diet or if they appear unable to comply with the dietary regimen they will 
            
        be followed to record the natural progress of the condition. Patients with other 
            
        forms of retinal degeneration, such as retinitis pigmentosa, fundus flavimacula- 
            
        tus. Juvenile retlnoschisls, are also examined and their courses are compared with 
            
        gyrate atrophy patients. 
            
         
            
        PH<; eO40 (Rav t/B4l 
            
         
            
        OPO 11 4-«ll 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00163-04 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO c/M'aclt'S or <»JS Titit must lil O" orn *n« btrwttn m» borOtrs ) 
            
         
            
        NIH Interinsti tute Medical Genetics Program: The Genetics Clinic 
            
         
            
        PRINCIPAL INVESTIGATOR (Lnt o4h»i pioltssionti parionnti tflo*/ the Prmapti InvttiigaiO' ) (Ntmt. W<e. laboritory. in<t miMuft «(T./i»i.o')> 
            
         
            
        PI; 
            
         
            
        Muriel I. Kaiser-Kupfer M.D. 
            
         
            
        Head, Section on Ophthalmic CB, NEI 
            
        Genetics and Pediatric 
            
        Ophthalmology 
            
         
            
        Others: Lessie McCain 
            
         
            
        R.N, 
            
         
            
        Clinical Technician 
            
         
            
        CB, NEI 
            
         
            
        COOPERATING UNITS (il »ny) 
            
         
            
        LAB^BRANCm 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and Pediatric Ophthalmology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN YEARS 
            
        .15 
            
         
            
        PROFESSIONAL 
            
         
            
        ,05 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        [3 (a) Human subjects 
            
        D (al) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues 
            
         
            
        D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use itinaa'0 unrtauceO type Do not txceed lt>e space proviOea ) 
            
         
            
        The Interinstit 
            
        by the Clinical 
            
        genetic disease 
            
        from all Instit 
            
        of genetic dise 
            
        seen, represent 
            
        high frequency 
            
        were evaluated 
            
        Clinic serves a 
            
        inherited or de 
            
         
            
        ute Medical Genetics Program and the Genetics Clinic, supported 
            
        Center, offer a multidiscipl inary approach to patients with 
            
        (Z01 CP 05139-0^^ CEB). Involved in the program are researchers 
            
        utes. Patients evaluated in the clinic reporsent a broad spectrum 
            
        ase. During the last year, approximately 'J23 individuals were 
            
        ing approximately 100 different disease categories. Due to the 
            
        of ocular involvement in many of the cases, almost all the patient 
            
        by Clinical Branch staff of were discussed in consultation. The 
            
        s a source of interesting case material concerning patients with 
            
        velopmental abnormalities of the visual system. 
            
         
            
        In addition to the Genetics Clinic, patients are seen for genetic consultation 
            
        at the Maryland School for the Blind. This experience has resulted the recruit- 
            
        ment of patients into Clinical Branch protocols. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00172- 04 CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO chtrtclers or (ejj Titit musi lil on one line Oelween the Ooros's ; 
            
         
            
        Senile Macular Degeneration 
            
         
            
        PRINCIPAL INVESTIGATOR (List ome- prolemont personne' Oeto* f^ Pnncipa: invesiigaw ) (Name, title laboratory ana institute atiliaiion/ 
            
         
            
        PI: Muriel I. Kalser-Kupfer M. D. 
            
         
            
        Others: Carl Kupfer 
            
        Monique Roy 
            
         
            
        Head, Section on 
            
         
            
        Ophthalmic Genetics CB, NET 
            
         
            
        M. D. Director NEI 
            
         
            
        M. D. Visiting Scientist CB, NEI 
            
         
            
        COOPERATING UNITS (it any) 
            
         
            
        None 
            
         
            
        LAB'BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and Pediatric Ophthalmology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, MD 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        O.'JS 
            
         
            
        PROfESSIONAL 
            
         
            
        0.^3 
            
         
            
        OTHER 
            
         
            
        0.00 
            
         
            
        CHECK APPROPRIATE BOXlES) 
            
         
            
        K (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        G (b) Human tissues D (c) Neither 
            
         
            
        Summary of work lUse startaarct unreduceo type Do not exceed fie space pro^iOeO I 
            
         
            
        This Study will determine if patients with severe visual loss because of 
            
        senile macular degeneration in one eye and with good vision in the second eye 
            
        can be protected from severe visual loss in the good eye by the administration 
            
        of vitamin E and vitamin C when exposure of the retina to light below 500 
            
        nanometers is diminished. The recruited patients will be randomly assigned 
            
        either to a treated or an untreated control group and examined at four-month 
            
        intervals. Follow-up will continue for five years, unless an early beneficial 
            
        or detrimental effect causes the study to be terminated in less than five 
            
        years. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00123-06-CB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (BO chtrtclt's <y leis Till* must lit on on* Una belvretn tht borOtn ) 
            
         
            
        Clinical Psychophysics of the Visual System 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi Olfe' prol»isionn pe'Sonrnl btlow tt)e Prmcipt' lnvtsl>gaior ) (Ntmt. Iitte. iMborHory. •no mniiule ilfilitlion) 
            
         
            
        PI; 
            
         
            
        Others: 
            
         
            
        Muriel I. Kaiser-Kupfer M.D. 
            
         
            
        Rafael C. Caruso 
            
        Kent E. Higgins 
            
        Ralph D. Gunkel 
            
         
            
        M.D. 
            
         
            
        Ph.D. 
            
         
            
        O.D. 
            
         
            
        Head, Section on C3, NEI 
            
        Ophthalmic Genetics 
            
        and Pediatric Ophthalmology 
            
         
            
        Visiting Scientist CB, NEI 
            
         
            
        Expert CB, NEI 
            
         
            
        Ophthalmic Physicist CB, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        LAB'BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Genetics and Pediatric Ophthalmology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN YEARS 
            
        .65 
            
         
            
        PROFESSIONAL 
            
        .35 
            
         
            
        OTHER 
            
         
            
        .3 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        E (a) Human subjects D (b) Human tissues D (c) Neither 
            
         
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        SUMMARY OF WORK ft/se slBnoa'O unrtducea type Do not exceed the space provided ) 
            
         
            
        The Visual function of patient with ocular diseases or lesions in the visual 
            
        pathways and of normal subjects is measured with psychophysical techniques. 
            
        These data are correlated with those obtained with electrophysiological tests 
            
        of visual function. The results stained contribute to the diagnosis of ocular 
            
        and neural disorders that affect vision, and are needed to characterize their 
            
        nature and evolution. They are also valuable in the assessment of the effect of 
            
        different forms of treatment on the outcome of these diseases. 
            
         
            
        DEPARTWEra OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT N'UVSER 
            
         
            
        Z01 EY 001i4i4-05-CB 
            
         
            
        "October"!, 1985 to September 30, 1986 
            
         
            
        TI'^Lt Qf P'^--'«^'LJ6-'' c.iji'acrf -s 0' Icii hi c m^j/ li: 01 ono line Oofneen trie borac'Z ) 
            
         
            
        Clinical Electropnysiology of the Visual System 
            
         
            
        PHifVCl^AL Ifn ESTIGATOR (Lisl olfte' p.-olen'onai personne' £k)'o« Cie Pnn: pal Invtsl.ga'o' ) (Namt, liHe. laboraioy. ana insliluta atijiaior) 
            
         
            
        PI: 
            
         
            
        Others; 
            
         
            
        Muriel I, Kaiser-Kupfer M.D. 
            
         
            
        Head, Section on Ophthalmic CB, NET 
            
        Genetics and Pediatric 
            
        Ophthalmology 
            
         
            
        Rafael Caruso 
            
        Kent E. Higgins 
            
        Doris J. Collie 
            
         
            
        M.D. 
            
         
            
        Ph.D. 
            
         
            
        A. A. 
            
         
            
        Visiting Scientist 
            
         
            
        Expert 
            
         
            
        Health Technician 
            
         
            
        CB, NEI 
            
        CB, NEI 
            
        CB, NEI 
            
         
            
        COOPEP.ATiNG UNITS ( .• anft 
            
         
            
        LA 
            
         
            
        ^iYn1 
            
         
            
        cal Branch 
            
         
            
        ^^^l 
            
         
            
        ion on Ophthalmic Genetics and Pediatric Ophthalmology 
            
         
            
        '■'^ftT,^ lifrf.^^Bei'hesda, Maryland 20892 
            
         
            
        TOT>^ WAN-YEARS 
            
         
            
        PROFESSIONAL 
            
         
            
        35 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES| 
            
         
            
        ^ (a) Human subjects D (b) Human tissues D (c) Neither 
            
         
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        S'j.'.'.WAni 0" V»OR-. ,Uie iiantta-a unreduced typt Do nol exceed ine space proviaeO.) 
            
         
            
        The visual function of patients with ocular diseases or lesions in the visual 
            
        pathways and of normal subjects is measured objectively with electrophysio- 
            
        logical techniques. These data are correlated with those obtained with psycho- 
            
        physical tests of visual function. The results obtained contribute to the 
            
        diagnosis of ocular and neural disorders that affect vision, and are needed to 
            
        characterize their nature and evolution. They are also valuable in the 
            
        assessment of the effects of different forms of treatment on the outcome of 
            
        these diseases. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        7.01 FY nn?n-m tr 
            
         
            
        PERIOD COVERED 
            
         
            
        npt-nhPf 1 , IQR^ r.n '^pptPfnhpr 30, 1Qfi6 
            
         
            
        TITLE OF PROJECT (BO chmracfrz oi wj] Trtit must tit or ont Unt o»rw»»n tht bonMrs ) 
            
         
            
        A nniihlp-Ma.'^l^prl rnnt.rnnpcl Ranflnml7.pn CHnloal Trial of Tnploal Cystpamlnp 
            
         
            
        PRINCIPAL INVESTIGATOR (UsI oir>t pro/tsstonH ptrsonnti b»lo» tr>» Principal Invtstigtlor ) (Nimt. t/ff*. iMtxymtoiy. tnd nstilult alfihation) 
            
         
            
        PI; 
            
         
            
        Others: 
            
         
            
        Muriel I. Kalser-Kupfer M.D, 
            
         
            
        Leasie McCain 
            
        Manuel Datlles 
            
         
            
        R.N, 
            
         
            
        M.D. 
            
         
            
        Head, Section on Ophthalmic 
            
        Genetics and Pediatric 
            
        Ophthalmology 
            
         
            
        Clinical Technician 
            
        Visiting Scientist 
            
         
            
        CB, NEI 
            
         
            
        CB, NEI 
            
         
            
        CB, NEI 
            
         
            
        COOPERATING UNITS fif •/!»■; 
            
         
            
        Human Genetics Branch, NICHD, National Institutes of Health, Bethesda, Maryland 
            
        (William Gahl , M.D., Ph.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on QphthaTmlc Genetics and Pediatric OphthaTmnl ogy 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NFT, NTH, Rpt.hP.^da, Mar>y1;:,nd ?nR 9? 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        .25 
            
         
            
        PROFESSIONAL 
            
         
            
        15 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        S (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (UsB slanCard unraCuC9<3 type Do not a*C99<J tha spaca proviOati ) 
            
         
            
        Nephropathic cystinosis is an autosomal, recessively inherited storage disease 
            
        in which nonprotein cystine accumulates within cellular lysosomes due to a 
            
        defect in lysosomal cystine transport. Ocular manifestations include photo- 
            
        phobia crystal deposits in cornea, conjunctiva iris and depigmentation of the 
            
        retina. Systemic complications include the Fanconi syndrome, and renal failure, 
            
         
            
        Eight years ago cysteamine, a free 
            
        Introduced in the therapy of cystin 
            
        improved growth and stabilized rena 
            
        on the accumulation of corneal crys 
            
        cells in tissue culture are readily 
            
        cysteamine, making feasible the use 
            
        vent the humoral route. After appr 
            
        tions which revealed none, we have 
            
        the efficacy of topical cysteamine 
            
        enrolled, outcome of the study awai 
            
         
            
        thiol which depletes cystine from cells, was 
            
        otic patients. Although patients had 
            
        1 function, there was no noticeable effect 
            
        tals. Recent studies showed that corneal 
            
        depleted of cystine by the introduction of 
            
        of topical ophthalmic cysteamine to circum- 
            
        opriate animal studies to test for complica- 
            
        begun a double-masked clinical trial to test 
            
        in humans. Five patients have thus far been 
            
        ts further observation. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        zm FY nnn fln-nR r.n 
            
         
            
        PERIOD COVERED 
            
         
            
        nptnhpr 1 , ^^P,'=, r.n .^ppt.Pmhpp ?n, iq86 
            
         
            
        TITLE OF PROJECT (80 ctiartclmrs or %3] Tim mul/ III or on* knt tMrwMn m« txyOtrj ) 
            
         
            
        Anr.prin r Chamhpr flnom ;illPs A.s.qno 1 ated with Glaucoma or Ocular Hypprtension 
            
         
            
        PRINCIPAL INVESTIGATOR (UsI olifi prol»iiioritl przonnl i»toi* me Pnncipl Inrtsiigalof j (Ntmn. btf. labornoty, ana nUiiult alfihaiion) 
            
         
            
        PI: 
            
         
            
        Carl Kupfer 
            
         
            
        Others: Muriel I. Kalser-Kupfer 
            
         
            
        Lessie McCain 
            
        Manuel B. Datiles 
            
        Paul Edwards 
            
         
            
        M.D. Director 
            
         
            
        M.D. Head, Section on 
            
         
            
        Ophthalmic Genetics 
            
         
            
        and Pediatric Ophthalmology 
            
         
            
        R.N. Clinical Technician 
            
         
            
        M.D. Visiting Scientist 
            
         
            
        M.D. Visiting Fe ll ow 
            
         
            
        NEI 
            
         
            
        CB, NEI 
            
         
            
        CB, 
            
        CB, 
            
         
            
        NEI 
            
        NEI 
            
         
            
        COOPERATING UNITS (il try) 
            
         
            
         
            
        LAB/BRANCH 
            
         
            
        Clinical Branch 
            
         
            
        SECTION 
            
         
            
        Section on QphthaTmio Qpnetlcs and Pedi atrip nphthalmnl ngy 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NFT, NTH, RpthPsda, Mar^yland ? n 8 9 ? 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.65 
            
         
            
        PROFESSIONAL 
            
         
            
        0.55 
            
         
            
        OTHER; 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        [3 (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Uu slandtrti urrtductO rype Do not axc»ed tha spaca prvviOad.) 
            
         
            
        With recent erabryological research indicating the role of the neural crest in 
            
        contributing to all connective tissues anterior to the lens epitheliura, the 
            
        group of developmental anomalies of the anterior chamber with glaucoma or 
            
        ocular hypertension is being reviewed. 
            
         
            
        ANNUAL REPORT 
            
         
            
        NATIONAL EYE INSTITUTE 
            
         
            
        October 1, 1984 - September 30, 1986 
            
         
            
        REPORT OF THE CHIEF, LABORATORY OF IMMUNOLOGY 
            
        Robert B. Nussenblatt, M.D. 
            
         
            
        . This past year was the first full year for the Laboratory of Immunology of 
            
        the National Eye Institute. The year saw the establishment of four Sections 
            
        within the Laboratory, each with its own Section Head: Section on Clinical 
            
        Immunology, Alan G. Palestine, M.D., Section on Immunology and Virology, John 
            
        J. Hooks, Ph.D., Section on Experimental Immunology, Igal Gery, Ph.D., and 
            
        Section on Immunoregulation, Robert B. Nussenblatt, M.D. 
            
         
            
        The Section on Clinical Immunology has been particularly interested in new 
            
        animal models for human intra-ocular inflammatory disease, as well as the role 
            
        of the neuro-endocrine axis on the immune response. The Section has added 
            
        insight into the underlying mechanisms of the intra-ocular inflammatory 
            
        disease produced by endotoxin immunization. Class II antigen expression by 
            
        nonimmune cells within the eye was noted in the iris and the ciliary body, 
            
        though no T-cells were present in the inflammatory infiltrate; gamma- 
            
        interferon, a T-cell product, is thought the most potent inducer of class II 
            
        expression. Though corticosteroid therapy abrogated both the cellular 
            
        infiltrate and class II expression, only the cellular infiltrate could be 
            
        prevented when indomethacin was utilized. The role of class II antigen 
            
        expression on nonimmune cells may play an important role in the localization 
            
        of the immune response. In separate studies examining the role of pituitary 
            
        hormones and their effect on the ocular immune response, the Section has noted 
            
        that modulation of this system appears to have profound effects on the immune 
            
        response. The concurrent use of bromocriptine, which blocks prolactin 
            
        production by the pituitary, with a dosage of cyclosporine that ordinarily is 
            
        not especially effective in preventing the S-antigen induced experimental 
            
        uveitis model, proved extremely effective, with complete protection affected. 
            
        These findings will have immediate clinical application, since manipulation of 
            
        the neuroendocrine system will hopefully permit the use of lower dosages of 
            
        cyclosporine, and thereby prevent cyclosporine induced nephrotoxicity. These 
            
        findings suggest that we are just beginning to learn about the possible 
            
        immunomodulative techniques which should lead to better therapeutic 
            
        strategies. 
            
         
            
        The Section on Experimental Immunology has been actively involved in the 
            
        evaluation of the immune response and how it relates to ocular antigens. The 
            
        Section has had the opportunity to compare two models of human uveitis induced 
            
        by two distinct retinally derived antigens, the retinal S-antigen and IRBP. 
            
        It has been noted that the susceptibility to these diseases is different in 
            
        lower mammals. Further, delineation of the new IRBP induced model revealed 
            
        that it was T-cell mediated and that the disease could be actively transferred 
            
        by lymphocytes. Further the disorder could be induced in monkeys. The 
            
        disease was a granulomatous uveitis, bearing characteristics similar to such 
            
        severe human conditions as sympathetic ophthalmia and Vogt-Koyanagi-Harada 's 
            
        disease . 
            
         
            
        The Section on Immunology and Virology has had a long term interest in the 
            
        production of T-cell immunomodulators, particularly interferon, and the role 
            
        these play in ocular structures. The group has recently demonstrated for the 
            
        first time the presence of IFN-gamma and IL-2 at the site of a localized 
            
        ocular autoimmune disease. Additionally, the evaluation of exocrine glands 
            
        involved in Sjogren's syndrome is infiltrated predominantly with T-cells, the 
            
        majority of which express class II antigens. Moreover, the glandular 
            
        epithelial cells (ducts and acini) were induced to express these antigens as 
            
        well. In order to better evaluate the retinal pigment epithelial cell, a cell 
            
        wit'h immune-like characteristics, the Section has produced the first 
            
        monoclonal antibody which is directed solely at the human RPE, with studies 
            
        using this new immune probe just beginning. 
            
         
            
        The Section on Immunoregulation has been evaluating, in an in vitro 
            
        system, the role of ocular cells in enhancing an immune response. The 
            
        development of T-cell lines specific to the retinal S-Ag, which are capable of 
            
        inducing uveitis when transferred to a naive host, has permitted the Section 
            
        to ask several questions concerning the interaction between immune cells and 
            
        the eye. A stable long-term rat Muller cell line has permitted the Section to 
            
        evaluate the interactions between these two pure cell populations. A profound 
            
        inhibitory effect by these cells on the T-cell has been seen, suggesting that 
            
        this may be a normal protection mechanism. However, alterations of the Muller 
            
        cells' membrane can obviate this inhibitory effect. Understanding basic 
            
        mechanisms in parasitic conditions has also been a major concern of the 
            
        Section, particularly toxoplasmosis and onchocerciasis. Indeed, in the first 
            
        immunohistologic study of ocular onchocerciasis, the group has seen that 
            
        T-cells are the predominant immune cell present and that vascular endothelia, 
            
        pericytes and fibroblasts in the eye express class II antigens. Studies in 
            
        the use of cyclosporine for human intra-ocular inflammatory disease has 
            
        yielded important information concerning the nephrotoxic effects of the drug. 
            
        Renal biopsies of patients on cyclosporine have demonstrated alterations in 
            
        renal morphology, supporting the concept that there is a reversible as well as 
            
        an irreversible component to this secondary effect of the drug. Newer 
            
        therapeutic strategies, such as the use of bromocriptine combined with 
            
        cyclosporine as well as new attempts at evaluating the local efficacy of this 
            
        drug are underway. 
            
         
            
        The Laboratory of Immunology's first year has produced significant 
            
        observations both from a clinical and basic research point of view. A better 
            
        understanding of the basic mechanisms of ocular inflammatory disease is 
            
        imperative, and the groundwork has now been laid. Further, as with our 
            
        initial observations with cyclosporine, we sincerely feel that the 
            
        Laboratory's work will result in better directed and more effective therapies 
            
        for a group of diseases that are most challenging. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PRCJJECT NUMBER 
            
         
            
        ZOl EY 00229-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT ISO chartcien <y less Titit must tit on one Ime between me t>OfOe'S I 
            
         
            
        Assessment of the Size of the Leak Induced in Retinal Vessels Using PITC-Dextrans 
            
         
            
        PRINCIPAL INVESTIGATOR iUsi othe' prolessionei persome beio» rftt Pnncipt. investigero- i (Name title laboratory and mstitute aHiiiaiioni 
            
         
            
        PI: Susan Lightman M.D. Visiting Fellow LI, NEI 
            
         
            
        Others: Alan G. Palestine M.D. 
            
        Einar Stefansson M.D. 
            
         
            
        Head, Section on Clinical 
            
         
            
        Immunology 
            
        Visiting Scientist 
            
         
            
        LI, NEI 
            
        CB, NEI 
            
         
            
        COOPERATING UNITS (it any) 
            
         
            
        LAE'BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Clinical Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.5 
            
         
            
        PROFESSIONAL 
            
        0.5 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ESi 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        en (a2) Interviews 
            
         
            
        C (b) Human tissues E (c) Neither 
            
         
            
        Summary of work (Use stanoa'c unreauceo type Dc no; eiceoo tne space provioea i 
            
         
            
        Uveitis was induced in two monkeys by immunization with IRBP and serial 
            
        fluorescein angiograms performed using different sized dextrans linked to 
            
        fluorescein. The aim of these studies is to provide data on the retinal vessels 
            
        and toxicology data to enable these agents to be used in humans. We have 
            
        demonstrated that the larger molecular weight dextrans are less permeable than 
            
        sodium fluorescein in the inflamed retina. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl n 00230-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO cttaracierz or less Title must In or one line between itie boroers i 
            
         
            
        Quantitative Assessment of Retinal Vascular Permeability 
            
         
            
        PRINCIPAL INVESTIGATOR (US! ottte' prolessiont personnel below me Pnncipel Investigator ) INBme title laboratory and mstnute iltihatton) 
            
         
            
        PI: Susan Lightman M.D. Visiting Fellow LI, NEI 
            
         
            
        Others; 
            
         
            
        Alan G. Palestine M.D. 
            
         
            
        Head, Section on Clinical 
            
        Immunology 
            
         
            
        LI, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        Laboratory of Neurosciences, National Institute on Aging (Emanuel Rechthand, 
            
        M.D.); Laboratory of Neurosciences, National Institute on Aging (Stanley 
            
        Rapoport, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Clinical Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-VEARS 
            
        0.08 
            
         
            
        PROFESSIONAL 
            
         
            
        0.08 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOXlESi 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        n (a2) Intervievi/s 
            
         
            
        G (b) Human tissues ^ (c) Neither 
            
         
            
        Summary of work (Use slanaera unreOtjcea type Do not etceed the space provided ) 
            
         
            
        A sensitive quantitative method was set up for examining the permeability of 
            
        retinal vessels in the rat. Baseline values for normal rat retinal vessels were 
            
        established and the method will be applied to pathological situations. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00217-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 characters O' >tSi Title must fit on one line between ttie txtrOers ) 
            
         
            
        Lymphocyte Migration in Experimental Autoimmune Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi other prolessional personnel below the Pnncipai Investigato' ) (Name title, laboratory ana institute afliiiationi 
            
         
            
        PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        Deputy Clinical Director NEI 
            
         
            
        Chemist LI, NEI 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        Others: Robert B. Nussenblatt M.D. 
            
        ■__ Consuelo Muellenberg-Coulombre 
            
         
            
        Myung Kim M.D. 
            
         
            
        Susan Lightman M.D. 
            
         
            
        COOPERATING UNITS (H any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Clinical Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 
            
         
            
        20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.3 
            
         
            
        PROFESSIONAL 
            
         
            
        0.3 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues £ (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standard unreduced type Do not exceed ttie space provided ) 
            
         
            
        Experimental autoimmune uveitis (EAU) is induced by immunization of rats and 
            
        other experimental animals with S-antigens (a soluble antigen from the retina) 
            
        is being investigated in this laboratory as a model of human intra-ocular 
            
        inflammation. This experimental inflammation can be transferred from donor 
            
        rats to naive recipients using lymphocytes harvested from the spleen or lymph 
            
        nodes. Following harvesting of the cells from the donors and three days in 
            
        culture with stimulating antigen, the cells are injected into the 
            
        intra-peritoneal cavity and five to seven days later the recipient rats develop 
            
        EAU. The disease can also be transferred using a T-helper cell line by 
            
        intra-peritoneal or intra-ocular injection. The mechanism of transfer of 
            
        disease is unclear. This work has used radioactively labeled lymphocytes to 
            
        determine the fate of these lymphocytes after injection into the peritoneal 
            
        cavity or blood during the process of the development of uveitis. The goal of 
            
        this project is to understand the initiating mechanisms of inflammation in the 
            
        hope that these mechanisms can be extended and applied to human inflammations. 
            
        Thus far we have determined that only a small percentage of the lymph node 
            
        lymphocytes injected into the peritoneal cavity actually reach the eye during 
            
        the induction of EAU. Of 100 million cells transferred into the peritoneal 
            
        cavity, approximately 5,000 reach the eye. Many more reach the spleen, liver 
            
        and thymus however. The work is now being extended to study the migration 
            
        patterns of intra-peritoneal or intra-ocular T-cell lines. 
            
         
            
        PHQ AA4n /Rttij MtiA\ 
            
         
            
        ! PROJECT NUMBER 
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
         
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        ZOl EY 00218-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to Sept ember 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characters or less Title must tit on one line between the txytters ) 
            
         
            
        Human T-cell Leukemia/Lymphotropic Virus Type 111 and Eye Disease 
            
         
            
        PRINCIPAL INVESTIGATOR (Lai other prolesiionai personnel below the Principal Investigalor ) (Name. tnie. laboratory. arxJ mstnute altiiiationj 
            
         
            
        PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        Others; Leslie S. Fujikawa M.D. Senior Staff Fellow LI, NEI 
            
         
            
        Robert B. Nussenblatt M.D. Deputy Clinical Director NEI 
            
         
            
        Myung Kim M.D. Visiting Fellow LI, NEI 
            
         
            
        COOPERATING UNITS (K any) Laboratory of Tumor Cell Biology, National Cancer Institute (S. 
            
        Zaki Salahuddin, Ph.D.); Laboratory of Cellular & Molecular Biology, National 
            
        Cancer Institute (Dharam Ablashi, D.V.M.); Department of Critical Care Medicine, 
            
        Clinical Center (Henry Masur, M.D.); Laboratory of Tumor Cell Biology, National 
            
         
            
        LAB/BRANCH Cancer Institute (Robert C. Gallo, M.D.) 
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Clinical Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.91 
            
         
            
        PROFESSIONAL 
            
         
            
        0.91 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOXfESi 
            
         
            
        B (a) Human subjects □ (b) Hunnan tissues □ (c) Neither 
            
         
            
        D (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided ) 
            
         
            
        HTLV-III was Studied in ocular fluids and cells in order to characterize its 
            
        possible involvement in ophthalmic disease in AIDS and possible transmissibility 
            
        through ocular fluids. 
            
         
            
        a. HTLV-III was isolated from the tear fluid of patients with AIDS by using 
            
        Schinner's filter paper strips and infection of lymphocytes plus 
            
        retransmission to other lymphocytes. 
            
         
            
        b. Studies indicate that conjunctival epithelial cells from AIDS patients 
            
        contain HTLV-III and may therefore serve as a reservoir for the virus. 
            
         
            
        c. Further studies suggest more widespread presence of HTLV-III in 
            
        ocular tissue such as the cornea and vitreous. 
            
         
            
        Patients with AIDS and cytomegalovirus retinitis were studied to improve therapy 
            
        for this blinding disorder. Laser therapy for active lesions was ineffective, 
            
        but the antiviral drug DHPG was effective in treating but not curing the 
            
        infection . 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00219-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        Orrober 1. 1985 to September 30. 1986 
            
         
            
        TITLE OF PROJECT (BO charaaars or his Titta must In or one hnt berwaan the borOars ) 
            
         
            
        The Effect of Bromocriptine on Human Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi oiha' prolaiuonal partonnal balow tha Pmapal Invasligalor ) (Nama. btle. laboratory, and nitituta atliiialion) 
            
         
            
        PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        Others: Consuelo Muellenberg-Coulombre 
            
         
            
        Myung Kim M.D. 
            
         
            
        Robert B. Nussenblatt M.D. 
            
         
            
        Chemist LI, NEI 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        Deputy Clinical Director NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        Metabolism Branch, National Cancer Institute (Marie C. Gelato, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Clinical Iimnunologv 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.29 
            
         
            
        PROFESSIONAL 
            
         
            
        0.29 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOXlES) 
            
         
            
        E (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use slanaard unreduced type Do not etceed (Tic space provided ) 
            
         
            
        In recent years there has been increasing evidence in the literature that 
            
        pituitary horrnones are capable of regulating the iiranune system. There is 
            
        evidence to suggest that prolactin is an immunostimulatory hormone and that 
            
        reduction of serum prolactin levels in experimental animals by hypothesectomy or 
            
        bromocriptine will result in a degree of immunosuppression. 
            
         
            
        This information has been applied to humans and two clinical studies have begun 
            
        Both of these are in early phase of patient recruitment. One study is a 
            
        randomized trial between placebo and bromocriptine in recurrent anterior uveitis 
            
        using the end point of the number of recurrences per year to determine whether 
            
        or not bromocriptine is capable of regulating the immune system in these 
            
        patients. The second trial focuses on the additive effects of cyclosporine plus 
            
        bromocriptine in attempts to treat patients with posterior uveitis at lower 
            
        doses of cyclosporine in order to reduce its concurrent renal toxicity while at 
            
        the same time achieving an immunosuppressive effect . Cyclosporine and prolactin 
            
        compete for binding sites on the lymphocyte. 
            
         
            
        Further studies in human disease will hopefully elucidate other aspects of the 
            
        neuroendocrine axis which can be utilized to regulate the immune system to treat 
            
        autoimmune diseases . 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00220-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJHCT igo cf<aract»rs or lau Trt* must tn or ont hnt btrwtfi tht borxfrj ) 
            
         
            
        Endocrine Modulation of Immune-Mediated Eve Disease in Rats 
            
         
            
        PRINCIPAL INVESTIGATOR (Lai otfmr proltiSKinU p»rsonntl Otlow m« Pnncipti Invstigttor ) (Nam*, 0O9 laboruiory arxj mstrtutt atfthtnon) 
            
         
            
        PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        Others: Consuelo Muellenberg-Coulombre 
            
         
            
        Myung Kim M.D. 
            
         
            
        Robert B. Nussenblatt M.D. 
            
         
            
        Chemist LI, NEI 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        Deputy Clinical Director NEI 
            
         
            
        COOPERATING UNITS (it tny) 
            
         
            
        Metabolism Branch, National Cancer Institute (Marie C. Gelato, M.D.) 
            
         
            
        LAB/8 RANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Clinical Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 
            
         
            
        20892 
            
         
            
        TOTAL MAN- YEARS 
            
        0.89 
            
         
            
        PROFESSIONAL 
            
         
            
        0.89 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (ai) Minors 
            
        C (a2) Intervievifs 
            
         
            
        C (b) Human tissues 
            
         
            
        S (c) Neither 
            
         
            
        SUMMARY OF WORK (Us« sttnOMrx] unreduced type Do not etcoeO ttit space provioao ) 
            
         
            
        In recent years there has been increasing evidence in the literature that 
            
        pituitary hormones are capable of regulating the immune system. There is 
            
        evidence to suggest that prolactin is an immunostimulatory hormone and that 
            
        reduction of serum prolactin levels in experimental animals by hypothesectomy or 
            
        bromocriptine will result in a degree of immunosuppression. 
            
         
            
        An animal model of experimental autoimmune uveitis (EAU) induced by immunization 
            
        of rats with S-antigen (a soluble antigen from the retina) is used as a model 
            
        for intraocular inflammatory disease. We have demonstrated that concurrent 
            
        antibody production in both males and females and the incidence of uveitis in 
            
        female animals but did not have a significant effect on the immune responses 
            
        measured by lymphocyte proliferation. As reported before, cyclosporine in high 
            
        doses (10 mg/kg) there is only partial effect. We have demonstrated that the 
            
        concurrent use of bromocriptine to suppress prolactin in combination with low 
            
        dose cyclosporine is more effective than either drug separately in suppressing 
            
        both the incidence of disease as well as the cellular and humoral immune 
            
        responses to immunization. There is evidence in the literature to suggest that 
            
        cyclosporine is able to compete for binding on the lionphocyte by prolactin and 
            
        that reductions in prolactin level may therefore make cyclosporine more 
            
        effective. Further studies in animal disease will hopefully elucidate other 
            
        aspects of the neuroendocrine axis which can be utilized to regulate the immune 
            
        system to treat autoimmune diseases. 
            
         
            
        Due £/v^n lam^. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00221-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characters or less Title must In on one line between the borOers ) 
            
         
            
        Intraocular Class II Antigen Expression in Endotoxin-Induced Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (USI other professional personnel below the Pnnapel Investigator ) (Name, title, laboratory, and institute atliliation) 
            
         
            
        PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        Others: Myung Kim M.D. 
            
         
            
        Consuelo Muellenberg-Coulombre 
            
        Robert B. Nussenblatt M.D. 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        Chemist LI, NEI 
            
         
            
        Deputy Clinical Director NEI 
            
         
            
        COOPERATING UNITS fit any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Clinical Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 
            
         
            
        20892 
            
         
            
        TOTAL MAN- YEARS 
            
        0.51 
            
         
            
        PROFESSIONAL 
            
         
            
        0.51 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (al) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues 
            
         
            
        E (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanOara unreduced type Do not exceed the space provided ) 
            
         
            
        Endotoxin is a polysaccharide derived from the cell wall of gram negative 
            
        bacteria. When injected into the footpad or the eye of a rat it will induce an 
            
        inflammatory reaction within the eye. Endotoxin injection in the footpad does 
            
        not lead to inflammation in other organs but does produce bilateral uveitis 
            
        primarily centered at the ciliary body and iris. The mechanism of this 
            
        inflammation is still unclear. However, since several types of anterior uveitis 
            
        in humans appear to be linked to gram negative bacteria exposure, this is 
            
        considered a relative model for anterior uveitis in humans such as Reiter's 
            
        syndrome. In this study rats received E. coli endotoxin and the expression of 
            
        class II antigens was studied within the eye using immunohistochemical 
            
        techniques. We observed that the expression of class II antigens on the ciliary 
            
        body and iris preceeded the influx of inflammtory cells into the eye and that 
            
        the inflammatory cells that entered the eye were primarily neutrophils with some 
            
        monocytes. No T-cells were present in the inflammatory infiltrate. The 
            
        expression of class II antigens within the eye was restricted to the iris and 
            
        ciliary body during this inflammatory episode and did not involve the retinal 
            
        pigment epithelium or retinal vessels. The inflammatory cellular infiltrate 
            
        could be inhibited by indomethacin or colchicine, however this did not alter the 
            
        expression of class II antigens by the iris or ciliary body indicating that this 
            
        expression is not simply a consequence of the inflammatory infiltrate but may be 
            
        intimately involved with the mechanism of the expression of endotoxin induced 
            
        uveitis. Corticosteroids were capable of suppressing both the cellular 
            
        inflammatory infiltrate and the expression of class II antigens. The expression 
            
        of class II antigens on nonlymphoid cells within the eye may be important in 
            
        antigen presentation or may simply signal a phenotypic change on the cells due 
            
        to the interaction of endotoxin with the cell membranes. 
            
         
            
        Dt-ic £/\j/\ m.. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00231-OJ LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO cfttrmcmrs oi ma Tm» must tit on on» Imt bttwaan the banters ) 
            
         
            
        Cell Surface Antigens on Retinoblastoma Cells 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust otfwr pnjltsstonn p»rsonntl btlow tt>« Principal Irtvas'igatiy j (Name. trOe latxiratoty ant) msWi/te atliUanon) 
            
         
            
        PI: Barbara Detrick Ph.D. Exoert LI, NEI 
            
         
            
        Others: John J. Hooks Ph.D. 
            
         
            
        Gerald J. Chader Ph.D. 
            
         
            
        Merlyn Rodrigues M.D., Ph.D. 
            
         
            
        Chi-Chao Chan M.D. 
            
         
            
        Head, Section on Imraunologv LI, NEI 
            
         
            
        and Virology 
            
        Chief LVR, NEI 
            
         
            
        Head, Section on Clinical LOp, NEI 
            
         
            
        Eye ■Pathologv 
            
        Staff Ophthalmologist LI, NEI 
            
         
            
        COOPERATING UNITS ((t any) 
            
         
            
        Duke University, Durham, North Carolina (Barton F. Haynes, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Imraunologv 
            
         
            
        SECTION 
            
         
            
        Section on ETCoerimental Immunologv 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.75 
            
         
            
        PROFESSIONAL 
            
         
            
        0.75 
            
         
            
        OTHER: 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        S (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        B (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanaanJ unreduced type Do not etceed the space provided ) 
            
         
            
        Class II antigens (HLA-DR and HLA-DQ) are membrane bound glycoproteins encoded 
            
        by genes in the major histocompatibility complex. In addition to their well 
            
        established role as regulatory molecules of the immune response, these 
            
        determinants are now suspected of playing an influencial part in cellular 
            
        differentiation . 
            
         
            
        In exploring the cellular composition of a popular childhood tumor, 
            
        retinoblastoma, we have had an opportunity to describe class II antigens on a 
            
        population of undifferentiated malignant cells of the retina. This study 
            
        provides the initial description of class II antigens on retinoblastoma cells. 
            
        Furthermore, HLA-DR antigen was found to be coexpressed on cells that contained 
            
        both neuronal and glial markers. This study also identifies for the first time 
            
        the presence of class II antigens on cells of neuronal origin. 
            
         
            
        Based on these initial studies, two areas will be explored. The first approach 
            
        will focus on the possible role of class II antigens in the cellular 
            
        differentiation or immune reactivity. The second will examine the prognostic 
            
        significance of these molecules on retinoblastoma cells and the possible 
            
        relationship class II proteins may have to the modulation and management of this 
            
        tumor. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00235-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OP PROJECT (80 charactarz of Wu Tint must ht on ont hne b»tw»en tr» borOtn ) 
            
         
            
        Identification and Modulation of Class II Antigens 
            
         
            
        PRINCIPAL INVESTIGATOR (Lat otntr proftsiional p»rsonnti £)»<ow tht Principal Inytstigator j (Namt. vot labomiory. ana nstnui9 atliiiHioni 
            
         
            
        PI: Barbara Detrick Ph.D. Expert LI, NEI 
            
         
            
        Others: John J. Hooks Ph.D. 
            
         
            
        Chi-Chao Chan M.D. 
            
         
            
        Leslie Fujikawa M.D. 
            
         
            
        Richard Wetzig M.D. 
            
         
            
        Caroline Percopo A.B. 
            
         
            
        Head, Section on Immunology 
            
         
            
        and Virology 
            
        Staff Ophthalmologist 
            
        Senior Staff Fellow 
            
        Senior Staff Fellow 
            
        Biologist 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        COOPERATING UNITS f* jnw Eye and Ear Infirmary, University of Illinois, Chicago, Illinois 
            
        (M.O.M. Tso, M.D.): Duke University, Durham, North Carolina (Barton F. Haynes, 
            
        M.D.); Paris, France (Laurence Boumsell, M.D.): and Paris, France (Alain 
            
        Bernard, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Experimental Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH, Bethesda. Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
        0.6 
            
         
            
        PROFESSIONAL 
            
        0.5 
            
         
            
        OTHER 
            
         
            
        0.1 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        C (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        E (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Uie Slanoanj unr^OuceO type Do not axca«a rtte ipace provtOea ) 
            
         
            
        Class II antigens are merrirane bound glycoproteins that are encoded by genes in 
            
        the mixed histocompatibility complex (MHO) . The expression of these antigens 
            
        allows a cell to participate in the initiation and perpetuation of immune 
            
        responses. Furthermore, although most cells that constitutively express class 
            
        II antigens are members of the immune system, other cell types can be induced to 
            
        demonstrate these molecules under selected conditions, such as an immunologic or 
            
        degenerative event. Early investigations demonstrated that patients with the 
            
        retinal degenerative disorder retinitis pigmentosa had a unique alteration in 
            
        two regulatory proteins, interferon-gamma and the MHC class II antigen, HLA-DR. 
            
        In addition, in vitro studies revealed that a regulatory cell in the eye, the 
            
        rpe cell, could also express this antigen and that these determinants were 
            
        sensitive to modulation with interferon-gamma. Based on these findings we 
            
        expanded our studies to evaluate class II antigen expression in ocular diseases. 
            
        We found that the rpe cell does not express class II antigen in the normal eye. 
            
        In contrast, the rpe cell did express these molecules in a retinal degenerative 
            
        disorder (retinitis pigmentosa) and in two ocular inflammatory diseases 
            
        (sympathetic ophthalmia and uveitis) . Using the EAU animal model of ocular 
            
        autoimmune disease we demonstrated that the rpe cell is activated to express 
            
        class II antigens prior to clinical and histopathological evidence of the 
            
        disease. We are now evaluating the effects of such modulators as 
            
        interferon-gamma, anti-la antiserum and cyclosporine on class II antigen 
            
        expression with the hope that an alteration in activation or expression of these 
            
        molecules may modify the disease process to the benefit of the host. 
            
        In summary, these studies indicate that the appearance and modulation of class 
            
        II antigens may play a role in the initiation, maintenance or regulation of 
            
        pathologic events in degenerative or inflammatory processes. 
            
         
            
        DljC c/\jn ;Oa.. « fB.«\ 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00069- 09 LI 
            
         
            
        ScTo^er^'^f f 1 985 to September 30. 1986 
            
         
            
        JITlE op PROJECT (80 cnaraclen or less. Title must Kor one Ime between ttte bonJers ) 
            
        mmune Responses to ocular Antigens 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust Other prolessionai personnel below the Pnncipal Investigator ) (Name title laboratory, and mstilule aMaiioni 
            
         
            
        PI: Igal Gery Ph.D. Head, Section on Experimental LI, NEI 
            
         
            
        Head, Section on Experimental 
            
        Immunology 
            
         
            
        Others: 
            
         
            
        Shlgeto Hirose M.D. 
            
         
            
        Cathy McAllister Ph.D. 
            
         
            
        Barbara Vistica B.A. 
            
         
            
        Gregory Fox B.A. 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        Extramural Fellow LI, NEI 
            
         
            
        Microbiologist LI, NEI 
            
         
            
        HHMI-NIH Research Scholar LI, NEI 
            
         
            
        COOPERATING UNITS (I'anyl 
            
         
            
        Tokyo Medical College Hospital, Tokyo, Japan (Dr. M. Usui) 
            
         
            
        LAB'BRANCH 
            
         
            
        Laooratory of Immunology 
            
         
            
        SECTION 
            
         
            
        section on Experimental Immunology 
            
         
            
        fSfrM^^t^°e'^sda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        2.7 
            
         
            
        PROFESSIONAL 
            
         
            
        OTHER 
            
         
            
        0.6 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        n (a2) Interviews 
            
         
            
        D (b) Human tissues B (c) Neither 
            
         
            
        SUMMARY OF WORK (Use slenoara unreduced type Do not exceed the space provided ) 
            
         
            
        This project is aimed at learning about the pathogenesis of immune-mediated 
            
        eye diseases, mainly by investigating the animal disease, "experimental auto- 
            
        immune uveitis" (EAU), which is induced in various animals by immunization with 
            
        certain eye components. EAU is considered a model for certain human ocular 
            
        conditions. Research during FY 1986 has focused on EAU induced by interphoto- 
            
        receptor retlnoid-binding protein (IRBP). Our previous study (FY-1985) showed 
            
        that IRBP is highly uveitogenic in Lewis rats. Major new findings include: (1) 
            
        Rats of different inbred strains vary in their susceptibility to EAU induced by 
            
        IRBP or by another retinal protein, S-antigen (S-Ag). This finding shows that 
            
        the susceptibility to EAU is related to genetic makeup and supports the assump- 
            
        tion that the susceptibility to immune-mediated diseases in man is also 
            
        genetically regulated. (2) The pathogenic mechanism of IRBP-induced EAU was 
            
        found to be cell mediated: the disease could be adoptively transferred by 
            
        lymphocytes and a correlation was found between EAU development and cellular 
            
        immunity but not with antitxsdy production, (3) Monkey IRBP was found to be 20 
            
        times less uveitogenic in rats than bovine IRBP. The two IRBPs showed cross 
            
        reactivity when used for stimulation of lymphocytes for EAU Induction, but did 
            
        not cross react by the lymphocyte proliferation assay. This finding indicates 
            
        that lymphocyte responses in vitro do not necessarily represent their capacity to 
            
        induce disease in vivo. iU) Monkeys were found highly susceptible to IRBP- 
            
        induced EAU. This monkey disease is of special interest by showing a close 
            
        similarity to certain ocular diseases in man, in particular sympathetic 
            
        ophthalmia and Vogt-Koyanagl-Harada disease. Similarly to these human diseases, 
            
        IRBP-induced in monkey was expressed mainly as granulomatous choroiditis. In 
            
        addition to providing a useful model for the human diseases, the findings with 
            
        IRBP-induced EAU in monkeys support the notion that autoimmune processes to 
            
        retinal antigens participate in the etiology of certain human eye diseases. 
            
         
            
        I PROJECT NUMBER 
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
         
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        Z01 EY 0023-08 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (80 ctfractarz of lets Title mus; fn or one hne Oerween itte Ixyae's I 
            
         
            
        Macrophage and Lyicphocyte Participation In Inflammatory Processes 
            
         
            
        PRINCIPAL INVESTIGATOR lUst oiKe' pnieaione: pertonnei beio* tf>e Pnncipa' Investigiior ) (Name title Mxyelory. tna nstnute •ffi'"«fion; 
            
         
            
        Head, Section on Experimental LI, NET 
            
         
            
        Immunology ' 
            
         
            
        Extramural Fellow LI, NEI 
            
         
            
        Microbiologist LI, NEI 
            
         
            
        PI: 
            
         
            
        I gal Gery 
            
         
            
        Ph.D 
            
         
            
        Others': 
            
         
            
        Cathy McAllister 
            
         
            
        Ph.D 
            
         
            
         
            
        Barbara Vistlca 
            
         
            
        B.A. 
            
         
            
        COOPERATING UNITS (H eny) 
            
         
            
        Laboratory of Developmental and Molecular Immunity, National Institute of Child 
            
        Health and Human Development (R. Sekura) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Experimental Immunology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH. Bethesda. Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.1 
            
         
            
        PROFESSIONAL 
            
         
            
        OTHER 
            
         
            
        0.1 
            
         
            
        CHECK APPROPRIATE BOX(ESl 
            
         
            
        C (a) Human subjects E (b) Human tissues IZ (c) Neither 
            
         
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        SUMMARY OF WORK (Use stanoara unreaucea type Do nof etceeo trie space provioec! i 
            
         
            
        This project has been aimed at collecting information concerning the processes' 
            
        which bring about inflammation and the Involvement of lymphocytes, macrophages 
            
        and Immune mediators in these processes. Experiments carried out this year have 
            
        further examined the effects of pertussis toxin (PT) on lymphoid cells in 
            
        culture. This bacterial product is a powerful adjuvant and it facilitates 
            
        remarkably the Induction of experimental autoimmune diseases. Our previous 
            
        experiments (FY 1985) have shown that PT stimulates lymphocytes and macrophages 
            
        in culture. Experiments carried out this year have indicated that PT has a dual 
            
        effect on these lymphoid cells. Thus, cultures of lymphocytes or macrophages 
            
        which are stimulated by other agents are often inhibited by the addition of PT at 
            
        doses which are slmulatory to cultures with no other stimuli. This finding is in 
            
        line with reports showing that, at certain circumstances, PT may both enhance and 
            
        Inhibit immune responses. 
            
         
            
        This project is being phased out, in order to focus the Section's effort on 
            
        Issues which relate directly to the Immunopathogenesis of ocular inflammatory 
            
        diseases (see project # 201 EY 00069-09). 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00232-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO chtrtctmrz or <•» TiO» must hi or ont /in* bttwtn m* Cxvda'3 ) 
            
         
            
        Interferon System in Cellular Function and Disease 
            
         
            
        PRINCIPAL INVESTIGATOR fL<Sf offw prol»ss>onaJ parsonntl btlow tt>a Principal Invtstigator ) (Hamt, otia Itxxmiory. anO msoiun MHii,aoon) 
            
         
            
        PI: John J. Hooks Ph.D. Head, Section on Immunology LI, NEI 
            
         
            
        and Virology 
            
         
            
        Others; Barbara Detrick Ph.D. 
            
         
            
        Caroline Percopo A.B. 
            
         
            
        Yotanna Dalavanga M.D. 
            
         
            
        I Chi-Chao Chan M.D. 
            
         
            
        Expert 
            
        Biologist 
            
        Visiting Fellow 
            
        Staff Ophthalmologist 
            
         
            
        LI, KEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        COOPERATING UNITS fit any) 
            
         
            
        New York University, School of Medicine, Department of Microbiology (Jan Vilcek, 
            
        M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunology and Virology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        1.A5 
            
         
            
        PROFESSIONAL 
            
         
            
        0.75 
            
         
            
        OTHER 
            
         
            
        0.7 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        11 (a) Human subjects 
            
         
            
        ID (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        n (b) Human tissues B (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standarx] unreduced rype Do not exceed ffie space provided ) 
            
         
            
        The IFN proteins can modify a variety of biological activities and are 
            
        considered one of the body's regulatory proteins. Numerous studies now indicate 
            
        that the IFN's are potent immunoregulators . During the past year we have been 
            
        studying the ways in which IFN proteins interact with cells of the inunune system 
            
        and how this interaction may modify immune responses and immunologically related 
            
        disorders . 
            
         
            
        Using immunocytochemical analysis we have developed a sensitive method of 
            
        identifying lymphokines, IFN-gamma and IL2, at the site of tissue damage. We 
            
        have identified the lymphokines/ IFN-gamma and IL2 in inflammatory eye diseases. 
            
        The presence of these lymphokines is associated with a lymphocyte infiltrate 
            
        predominantly of a T-cell origin and with the expression of MHC class II 
            
        antigens on both the infiltrating cells and in the retinal pigment epithelial 
            
        (rpe) cells. 
            
         
            
        This is the first demonstration of lymphokines, IFN-gamma and 112 at the site of 
            
        a localized autoimmune disease. These observations may indicate that IFN-gamma 
            
        induced MHC class II antigen expression may serve as a local amplification 
            
        system in autoimmune and inflammatory eye disease. A better understanding of 
            
        the role of lymphokines in the mechanisms involved in the development of 
            
        autoimmunity and inflammation may be beneficial in the treatment of these 
            
        diseases . 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl n 00232-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BC characttri ot tou 77»» musi M on on* lint bmtwttn mt t>on3trz ) 
            
         
            
        Interferon System in Cellular Function and Disease 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi otftur pnjItmonU pmrsonnti Da/ow lt>» Principal Invstigaior ) (Namt. or>e laOoraiory ana msotun altihation) 
            
         
            
        PI: John J. Hooks Ph.D. Head, Section on Immunology LI, NEI 
            
         
            
        and Virology 
            
         
            
        Others; Barbara Detrick Ph.D. 
            
         
            
        Caroline Percopo A.B. 
            
         
            
        Yotanna Dalavanga M.D. 
            
         
            
        Chi-Chao Chan M.D. 
            
         
            
        Expert 
            
        Biologist 
            
        Visiting Fellow 
            
        Staff Ophthalmologist 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        COOPERATING UNITS llf any) 
            
         
            
        New York University, School of Medicine, Department of Microbiologv (Jan Vilcek, 
            
        M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunology and Virology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        1.45 
            
         
            
        PROFESSIONAL 
            
         
            
        0.75 
            
         
            
        OTHER 
            
         
            
        0.7 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        D (b) Hunnan tissues EH (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanaarO uniwJucad type Do not 9tce«<3 ffie space proviOed ) 
            
         
            
        The IFN proteins can modify a variety of biological activities and are 
            
        considered one of the body's regulatory proteins. Numerous studies now indicate 
            
        that the IFN's are potent immunoregulators . During the past year we have been 
            
        studying the ways in which IFN proteins interact with cells of the immune system 
            
        and how this interaction may modify immune responses and immunologically related 
            
        disorders . 
            
         
            
        Using immunocytochemical analysis we have developed a sensitive method of 
            
        identifying lymphokines, IFN-gamma and IL2, at the site of tissue damage. We 
            
        have identified the lymphokines, IFN-gamma and IL2 in inflammatory eye diseases. 
            
        The presence of these lymphokines is associated with a lymphocyte infiltrate 
            
        predominantly of a T-cell origin and with the expression of MHC class II 
            
        antigens on both the infiltrating cells and in the retinal pigment epithelial 
            
        (rpe) cells. 
            
         
            
        This is the first demonstration of lymphokines, IFN-gamma and 112 at the site of 
            
        a localized autoimmune disease. These observations may indicate that IFN-gamma 
            
        induced MHC class II antigen expression may serve as a local amplification 
            
        system in autoimmune and inflammatory eye disease. A better understanding of 
            
        the role of lymphokines in the mechanisms involved in the development of 
            
        autoimmunity and inflammation may be beneficial in the treatment of these 
            
        diseases . 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        zo: n 00233-01 li 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30. 1986 
            
         
            
        TITLE OF PROJECT (60 characfrz o/ Isu TiOe must hi or oo« lina Oefwoen me tforaan ) 
            
         
            
        Studies on the Bioregulatory Aspects of the Retinal Pigment Epithelial Cell 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust othv profesiiona' personnel below f/w Pnncipei Investigator ) (Name, title latxyatory ana msvtjte alfihatxy, 
            
         
            
        Ph.D. Head, Section on Immunology LI, NET 
            
         
            
        and Virology 
            
         
            
        PI: 
            
         
            
        John J. Hooks 
            
         
            
        Others I Barbara Detrick Ph.D. 
            
         
            
        Caroline Percopo A.B. 
            
         
            
        Yotanna Dalavanga M.D. 
            
         
            
        Chi-Chao Chan M.D. 
            
        Garth Stevens. Jr. M.D. 
            
         
            
        Expert 
            
        Biologist 
            
        Visiting Fellow 
            
        Staff Ophthalmologist 
            
        Senior Staff Fellow 
            
         
            
        LI, NEI 
            
        LI, NEI 
            
        LI, NEI 
            
        LI. NEI 
            
        LI. NEI 
            
         
            
        COOPERATING UNITS (if any) 
            
         
            
        National Institute of Dental Research. Clinical Immunology Section (Siraganian 
            
        Reuben, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunology and Virology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        1.^ 
            
         
            
        PROFESSIONAL 
            
         
            
        1.1 
            
         
            
        OTHER 
            
         
            
        0.3 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        □ (a2) Interviews 
            
         
            
        E (b) Human tissues 
            
         
            
        D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standard unreduced type Do not exceed me space provided ) 
            
         
            
        The retinal pigment epithelial (rpe) cell is a major regulatory cell in the eye. 
            
        That is, the rpe cell exerts a variety of actions in maintaining retinal 
            
        integrity and function. In order to more effectively study this cell in vivo 
            
        and in vitro, we have produced monoclonal antibodies directed against human rpe 
            
        cells . 
            
         
            
        Using immunoperoxidase assays (ABC) , we have identified two mouse IgG monoclonal 
            
        antibodies which react with the hximan rpe cell. The monoclonal antibodies are 
            
        both specific for the rpe cell within the eye, since they do not react with any 
            
        other ocular structures. Moreover, these antibodies do not cross react with 
            
        human skin, kidney or peripheral mononuclear cells. 
            
         
            
        This is the first monoclonal antibody which is directed solely at the human rpe 
            
        cell. Further characterization and studies with this antibody should prove 
            
        useful in the identification of rpe cells in situ and in vitro. Moreover, this 
            
        immunoglobulin will allow us to probe the bioregulatory functions of the cell. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 0023^-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 charmcnn <x l»ss Tittt must tn on on* line 0»tw»»n ttf txyOa'5 ) 
            
         
            
        MHC Class II Antigens in the Pathogenesis of Inflammatory Diseases 
            
         
            
        PRINCIPAL INVESTIGATOR (Utl otfter proltssionm ptrtonnti tMlow tf>* Principal Invtsligalor ) (Name vtle. lattoratory ana mslitutt afilianon) 
            
         
            
        PI: John J. Hooks Ph.D. Head, Section on Immunology LI, NEI 
            
         
            
        and Virology 
            
         
            
        Others: Barbara Detrick Ph.D. 
            
         
            
        Yotanna Dalavanga M.D. 
            
         
            
        Chi-Chao Chan M.D. 
            
         
            
        Robert B. Nussenblatt M.D. 
            
         
            
        Expert 
            
         
            
        Visiting Fellow 
            
        Staff Ophthalmologist 
            
        Deputy Clinical Director 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        NEI 
            
         
            
        COOPERATING UNITS (it any) 
            
         
            
        loannina School of Medicine, loannina, Greece (Haralampos M. Moulsopoulos, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunology and Virology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 
            
         
            
        20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.56 
            
         
            
        PROFESSIONAL 
            
         
            
        0.56 
            
         
            
        OTHER: 
            
         
            
        CHECK APPROPRIATE BOXiES) 
            
         
            
        G (a) Human subjects 
            
        C (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues 
            
         
            
        (c) Neither 
            
         
            
        SUMMARY OF WORK /Use slandara unmduced type Do not atceed Oe space proviOe<3 ) 
            
         
            
        MHC class II antigens, HLA-DR in the human and la in the mouse, are membrane 
            
        bound glycoproteins that are encoded by genes of the major histocompatibility 
            
        complex. Expression of these antigens is of great functional importance for the 
            
        initiation and perpetuation of immune responses. In a number of immuno- 
            
        pathologic conditions HLA-DR antigen negative cells are stimulated to express 
            
        class II antigens. In these cases an immunologic role has been postulated for 
            
        the class II antigen expression. 
            
         
            
        During the past year, we have determined if class II antigens are expressed in 
            
        certain diseases and we have evaluated their possible role in autoimmune and 
            
        inflammatory diseases. Initial studies identified cells in the anterior segment 
            
        and cells in the retina (rpe cell) which express class II antigens during 
            
        inflammatory eye diseases. These studies have been extended to evaluate 
            
        Sjogren's syndrome. We found that the salivary gland in Sjogren's syndrome is 
            
        infiltrated predominantly by T-lymphocytes and that this is associated with 
            
        class II antigen expression on glandular epithelial cells. 
            
         
            
        These studies on MHC class II antigen expression in localized autoimmune 
            
        diseases provide evidence that the activation of these antigens may contribute 
            
        to the immunopathogenesis of these disease. 
            
         
            
        PHS 60*0 (Rav 1/841 
            
         
            
        apo m\ 4411 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 0018^-04 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30. 1986 
            
         
            
        TITLE OF PROJECT ISO chirtctars Of ksi Title must tit on oo« Une betwaen Itm txyOtrt ) 
            
         
            
        Cellular Mechanisms in Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (List other protesuonH personnel below the Prmctpei InrestigeiO' ) (Name, title, lebortlory, end mlilute eflikeion) 
            
         
            
        PI: Rachel Caspi Ph.D. Visiting Fellow LI, NEI 
            
         
            
        Others: Robert B. Nussenblatt M.D. 
            
         
            
        Francois Roberge M.D. 
            
         
            
        Chi-Chao Chan M.D. 
            
         
            
        William Leake M.S. 
            
         
            
        Susan Lightman M.D. 
            
         
            
        Myung Kim M.D. 
            
         
            
        Deputy Clinical Director 
            
         
            
        Visiting Associate 
            
         
            
        Staff Ophthalmologist 
            
         
            
        Biologist 
            
         
            
        Visiting Fellow 
            
         
            
        Visiting Fellow 
            
         
            
        NEI 
            
        LI, NEI 
            
        LI, NEI 
            
        LI, NEI 
            
        LI, NEI 
            
        LI. NEI 
            
         
            
        COOPERATING UNITS (it eny) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        1.02 
            
         
            
        PROFESSIONAL 
            
         
            
        1.02 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Inlerviewrs 
            
         
            
        n (b) Human tissues 
            
         
            
        □ (c) Neither 
            
         
            
        Summary of work (Use stenOne unreduced type Do not exceed tr>e spece provided ) 
            
         
            
        In vivo functional long-term T-cell lines and T-cell clones are developed and 
            
        maintained in vitro from both peripheral blood and ocular fluids of humans and 
            
        animals. The phenotype and functional properties of these cells, as well as 
            
        their interaction with ocular resident cells are being studied. The goal of 
            
        these studies will be to identify the immunoreactive cells and mediators 
            
        involved in the intraocular inflammatory process. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEAF?CH PROJECT 
            
         
            
        PRCUECT NUMBER 
            
         
            
        ZOl EY 00222-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 chtracltn or lt» Trtte must In on on* km bttw»»n ttm borOtn ) 
            
         
            
        Kinetics of T-lymphocytes in the Eves with Experimental Auroimmi.np ihro-ir-; 
            
         
            
        1 s 
            
         
            
        PRINCIPAL INVESTIGATOR (Uil oltwr prxylnnonal partonnti below tht Prmapal IrxftsligatO' ) (Name. bOa. laboratory, and ntUlula alliUauor^j 
            
         
            
        PI: Chi-Chao Chan M.D. Staff Ophthalmologist 
            
         
            
        Others: Igal Gery 
            
         
            
        Robert B. Nussenblatt 
            
         
            
        LI, NEI 
            
         
            
        Ph.D. Head, Section on Experimental LI, NEI 
            
         
            
        Immunology 
            
        M.D. Deputy Clinical Director NEI 
            
         
            
        COOPERATING UNITS (d any) 
            
         
            
        University of Tokyo, School of Medicine (Manabu Mochizuki, M.D.); Hadassah Hebrew 
            
        University Hospital, Department of Ophthalmology (David BenEzra, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
        Section on Immunoregulat ion 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 
            
         
            
        20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.07 
            
         
            
        PROFESSIONAL 
            
         
            
        0.07 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOK(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interview's 
            
         
            
        D (b) Human tissues Q (c) Neither 
            
         
            
        SUMMARY OF WORK (Uie slanaara unrvducecl type Do not eiceeC me space provided ) 
            
         
            
        Identity and topographic localization of immunocompetent cells in rats with 
            
        experimental autoimmune uveoretinitis were analyzed by immunohistochemical 
            
        studies. The lymphocyte population at the inflammatory sites was found to 
            
        change markedly during the course of disease. In the early stage, 
            
        T-helper/inducers are the predominant cells in the eye. A relative increase of 
            
        T-suppressor/cytotoxic cells in the late stage were observed. These kinetics 
            
        can be influenced by cyclosporine and dexamethosone treatment. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00223-01 LI 
            
         
            
        •ERIOD COVERED 
            
        October 1, 1985 to September 30. 1986 
            
         
            
        TTLE Of PROJECT (80 cfmracltrs or <iji TiOt muti til on ont kne tmtw»»n tttt bofMri ) 
            
         
            
        Expression of Class II Antigens in Ocular Inflammatory Disorders 
            
         
            
        >RINCIPAL INVESTIGATOR (UtI oinm' pro/tttjona: purtormtl tmlow trm Pnoapal Invtsligilor ) (N$me. otf. Mxxttory, and mttiMi itluittion) 
            
         
            
        PI: Chi-Chao Chan M.D. Staff Ophthalmologist 
            
         
            
        Others: Barbara Detrick Ph.D. 
            
         
            
        John J. Hooks Ph.D. 
            
         
            
        Leslie S. Fujikawa M.D. 
            
         
            
        Igal Gery Ph.D. 
            
         
            
        Expert 
            
         
            
        Head, Section on Immunology 
            
         
            
        and Virology 
            
        Senior Staff Fellow 
            
        Head, Section on Experimental 
            
         
            
        Immunolopv 
            
         
            
        LI, NEI 
            
         
            
        LI , NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        COOPERATING UNITS (i any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunologv 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        0.3 
            
         
            
        PROfESSIONAL 
            
         
            
        0.3 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues Q (c) Neither 
            
         
            
        SUMMARY OF WORK (Uit sianaa'a unnOuctO type Do not eiceeC the ipeoe pro^ioea ) 
            
         
            
        Expression of class II antigens on ocular nonlymphoid cells was evaluated in 
            
        experimental autoimmune uveoretinitis (EAU) by the immunoperoxidase technique. 
            
        Class II antigens on nonlymphoid cells were not detected from normal rats. 
            
        However, these antigens were detected on the retinal pigment epithelia and 
            
        ciliary body epithelia a few days prior to the development of clinical and 
            
        histopathological EAU. la antigen was noted on the retinal vascular endothelia 
            
        at the onset of cellular infiltration in the retina, and appeared on the corneal 
            
        keratocytes and scleral fibroblasts after the early stage of clinical EAU. 
            
         
            
        The study demonstrates that during the course of EAU the ocular nonlymphoid 
            
        cells can be activated to express class II antigens. This antigen expression 
            
        may be important in the initiation and perpetuation of immune reactivity in the 
            
        eye. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PRCUECT NUMBER 
            
         
            
        ZOl EY 00224-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT ISO c^aracltn or <»st TiOt must In on on* knt bttw—n tht borOen ) 
            
         
            
        Sympathetic Ophthalmia: Immunopatholog;ica] Findings 
            
         
            
        PRINCIPAL INVESTIGATOR (Usl othtr proltiuonal partonnti b»km (ft* Pnncjpal InyibgHor.) (N»me. oOe. Itxyilcyy. and rtsinutt alliuationj 
            
         
            
        PI: 
            
         
            
        Chi-Chao Chan 
            
         
            
        Others: Robert B. Nussenblatt M.D. 
            
        Leslie S. Fujikawa M.D. 
            
        Alan G. Palestine M.D. 
            
         
            
        Garth Stevens, Jr. 
            
         
            
        M.D. Staff Ophthalmologist 
            
         
            
        Deputy Clinical Director 
            
        Senior Staff Fellow 
            
        Head, Section on Clinical 
            
        Immunology 
            
        M.D. Senior Staff Fellow 
            
         
            
        LI, NEl 
            
         
            
        NEI 
            
        LI, NEI 
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        COOPERATING UNITS f* any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulat ion 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
        0.37 
            
         
            
        PROFESSIONAL 
            
         
            
        0.37 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES( 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        B (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Ui» tlandard unnOuctd type Do not txctaO th« tptce provxMO ; 
            
         
            
        Iiranunocompetent cells in the ocular tissues from six patients with a clinical 
            
        diagnosis of sympathetic ophthalmia were examined using the immunohistochemical 
            
        technique. The choroidal infiltrates were composed primarily of T-lymphocytes . 
            
        Different amounts of macrophages and 13 lymphocytes were present in each case. 
            
        A varied spectrum of immunopathological and histopathological findings may occur 
            
        in clinically diagnosed sympathetic ophthalmia. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00225-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30. 1986 
            
         
            
        TITLE OF PROJECT (BO cttvacltn or /kM Toiit must M on on* in* bttw—n tfw bonjarz ) 
            
         
            
        Post-Inflammatory Complications in Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi othtr /yoltuionai ptrionnl bmknt ttf Pnnap»l Invustigetor ) (N»mt. DM. ItJxxtlcyy. and ntblut* tltikioonl 
            
         
            
        PI: Chi-Chao Chan M.D. Staff Ophthalmologist 
            
         
            
        Others: Robert B. Nussenblatt M.D, 
            
         
            
        Leslie S. Fujikawa M.D. 
            
         
            
        Richard P. Wetzig M.D. 
            
         
            
        Francois Roberge M.D. 
            
         
            
        Deputy Clinical Director 
            
        Senior Staff Fellow 
            
        Senior Staff Fellow 
            
        Visiting Associate 
            
         
            
        LI, NEI 
            
         
            
        NEI 
            
        LI, NEI 
            
        LI, NEI 
            
         
            
        LI, NEI 
            
         
            
        COOPERATING UNITS (* tny) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunolopv 
            
         
            
        SECTION 
            
         
            
        Section on ImmunoreRulat ion 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-VEARS 
            
         
            
        0.19 
            
         
            
        PROFESSIONAL 
            
         
            
        0.19 
            
         
            
        OTHER 
            
         
            
         
            
         
            
        CHECK APPROPRIATE BO)yES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        B (b) Human tissues 
            
         
            
        D (c) Neither 
            
         
            
        SUMMARY OF WORK (Uie stmatrO um»duC9<l type Do not exceefl ttte tpace pfOvtOeO ) 
            
         
            
        Complications of post-inflammation in uveitis patients included destruction of 
            
        photoreceptors, gliosis, choroidal scar, and formations of cyclitic membrane, 
            
        snowbanking and preretinal membrane. Eyes enucleated from patients with end 
            
        stages of chronic anterior uveitis (formation of cyclitic membrane), pars 
            
        planitis (formation of preretinal membrane) were evaluated. Glial cells and 
            
        proliferating Muller cells were the major components in these membranes. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00226-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        rn'LE Of PROJECT (BO chtrtcnrs or Itu Jltlt must M on ont knt btlwun tht bontttt.) 
            
         
            
        Immunopathology of Ocular Onchocerciasis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi othtt proltsstonai ptnonntt bttow tht Pvnapti Invtstigtiot ) (Ntma. bt«. labortlofy. mno rtititutt tftiuation) 
            
         
            
        PI: Chi-Chao Chan M.D. Staff Ophthalmologist LI, NEI 
            
         
            
        Others: Robert B. Nussenblatt M.D. Deputy Clinical Director 
            
         
            
        NEI 
            
         
            
        COOPERATING UNITS (0 tn^j 
            
         
            
        National Institute of Allergy and Infectious Diseases, Clinical Parasitic 
            
        Diseases Section (Eric A. Ottesen, M.D.) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.2 
            
         
            
        PROFESSIONAL 
            
         
            
        0.2 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        B (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Uit ifnOarO unrtduc»<l type Do not »tcte<l (^e tptca proYtOeO ) 
            
         
            
        Ocular specimens and sera from 12 patients with onchocerciasis and 10 controls 
            
        were studied. A mild to moderate chronic inflammatory cellular infiltration was 
            
        present in the conjunctiva of the onchocerciasis patients. T-lymphocytes were 
            
        the predominant inflammatory cells with the T-suppressor subset being 
            
        significantly increased in the onchocerciasis patients when compared to 
            
        controls. In the onchocerciasis patients, the nonlymphoid cells in the 
            
        conjunctiva and iris, such as vascular endothelia, pericytes and fibroblasts, 
            
        showed an increase in expression of class II antigens. The anti-onchocerca 
            
        Volvulus antibodies in the sera and aqueous humor were significantly higher in 
            
        the patients compared to the controls. These findings suggest that T-cells are 
            
        important in the ocular immune response to onchocerca and that expression of 
            
        class II antigens on nonlymphoid cells and the humoral factors may all play a 
            
        critical role in ocular onchocerciasis. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00216-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characieri o> less Title must In on one hne between ttte borders ) 
            
        The Role of Fibronectin in Wound Healing In the Eye 
            
         
            
        PRINCIPAL INVESTIGATOR (Usl otf>er prolessionei personnel below lt>e Principal Investigator I (Name, title laboratory, ana nstitute atliiiationi 
            
         
            
        PI: Leslie S. Fujikawa M.D. Senior Staff Fellow LI, NEI 
            
         
            
        Others: Robert B. Nussenblatt M.D. 
            
        . Manuel Datiles M.D. 
            
         
            
        Deputy Clinical Director 
            
        Visiting Scientist 
            
         
            
        NEI 
            
        CB, KEI 
            
         
            
        COOPERATING UNITS (H any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.18 
            
         
            
        PROFESSIONAL 
            
         
            
        0.18 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE B0X(ES| 
            
         
            
        E (a) Human subjects 
            
        D (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanaaro unreduced type Do not exceed trie space provided ) 
            
         
            
        The role of fibronectin in corneal wound healing was studied both in man and in 
            
        experimental animals. Studies were carried out in order to characterize the 
            
        possible effect of fibronectin on facilitating wound healing of the epithelium 
            
        in rabbits. A randomized masked study will evaluate the effectiveness of 
            
        fibronectin drops in treating recurrent corneal epithelial defects in patients. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl n 00092-08 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30. 1986 
            
         
            
        TITLE OF PROJECT (BO cntrtcleri or less Title must tit on one line between trie borters ) 
            
         
            
        HLA, ABO, and B-cell Alloantigens and Ocular Inflammatory Disease 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust olfter protesstonai personnel Mtow ttie Principal Investigator ) (Name title laboratory, and mstiti/te affiliation) 
            
         
            
        PI: Robert B. Nussenblatt M.D. Deputy Clinical Director NEI 
            
         
            
        COOPERATING UNITS (It any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Imrnunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH, Bethesda, Maryland 
            
         
            
        20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.03 
            
         
            
        PROFESSIONAL 
            
         
            
        0.03 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        E (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        n (b) Human tissues 
            
         
            
        G (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanOard unreduced type Do not exceed the space provided ) 
            
         
            
        Patients with ocular toxoplasmosis, pars planitis, Behcet's disease, 
            
        chorioretinitis of unknown origin, are being studied to determine the phenotype 
            
        frequency of the HLA, ABO, and B-cell alloantigens. Because the B-cell 
            
        alloantigens or DR antigens are thought to play a role in the immunologic 
            
        response to antigens, these findings will complement other immune uveitis 
            
        studies being simultaneously carried out. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl n 00075-08 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 charicleri <y less Title must tn or ont line eefween t/>* bontert I 
            
         
            
        InnDune Functions in Ocular Diseases of Obscure Etiology 
            
         
            
        PRINCIPAL INVESTIGATOR fUSI ottttt proltsstonal perjonnti balow tfte Pnncipai Investigator ) (Name title, latxytlory and institute affiliation) 
            
         
            
        PI: Robert B. Nussenblatt M.D. Deputy Clinical Director 
            
         
            
        NEI 
            
         
            
        Others; 
            
         
            
        Alan G. Palestine 
            
         
            
        M.D 
            
         
            
        Chi-Chao Chan 
            
         
            
        M.D 
            
         
            
        William Leake 
            
         
            
        M.S 
            
         
            
        Shigeto Hirose 
            
         
            
        M.D 
            
         
            
        Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        Staff Ophthalmologist LI, NEI 
            
         
            
        Biologist LI, NEI 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        COOPERATING UNITS (it any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.86 
            
         
            
        PROFESSIONAL 
            
         
            
        0.26 
            
         
            
        OTHER 
            
         
            
        0.6 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        E (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        C (b) Human tissues G (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standard unrwJuceti type Do not exceed tt>e space provided ) 
            
         
            
        In vitro cellular immune functions and lymphocyte subsets are being studied in a 
            
        masked method in patients with ocular toxoplasmosis, pars planitis, Behcet's 
            
        disease, geographic choroiditis, and chorioretinitis of unknown origin. Crude 
            
        ocular antigens, as well as purified uveitogenic soluble antigen (S-antigen) and 
            
        IRBP of the retina, are being used in a lymphocyte microculture technique to 
            
        evaluate the presence of cellular immune memory to ocular tissues. In addition, 
            
        purified antigens from the toxoplasmosis organism are also being tested in this 
            
        in vitro system. A subgroup of patients with posterior uveitis has been 
            
        identified as having this immunologic memory. Lymphocyte subsets in the blood 
            
        and in the eye are being defined in these patients by monoclonal antibodies. 
            
        These results shed light on the basic mechanisms of uveitis and may be used as a 
            
        guide for specific immunologic therapy. In a small group of selected patients, 
            
        chorioretinal biopsies are performed to evaluate the on-going ocular immune 
            
        response . 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl E^' 00094-08 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characten or lets Tint must lit on one kne betweon me borOeri ) 
            
         
            
        Immune Mechanisms in Experimental Autoimmune Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi olf>e' professional personnel beio» Itte Prmctpai Investigator ) (Name Utle laboratory and msotule altiiiation) 
            
         
            
        PI: Robert B. Nussenblatt M.D. Deputy Clinical Director 
            
         
            
        NEI 
            
         
            
        Others: Igal Gery 
            
         
            
        Cathy McAllister 
            
        Barbara Vistica 
            
        William Leake 
            
         
            
        Ph.D. Head, Section on Experimental LI, NEI 
            
         
            
        Immunology 
            
         
            
        Ph.D. Extramural Fellow LI, NEI 
            
         
            
        B.A. Microbiologist LI, NEI 
            
         
            
        M.S. Biologist LI, NEI 
            
         
            
        COOPERATING UNITS (if any} 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Itnmunoregulat ion 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Marvland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
        0.75 
            
         
            
        PROFESSIONAL 
            
         
            
        0.35 
            
         
            
        OTHER 
            
         
            
        O.U 
            
         
            
        CHECK APPROPRIATE B0X(ES| 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        C (b) Human tissues 
            
         
            
        E (c) Neither 
            
         
            
        SUMMARY OF WORK (Use startdarti unreduced type Do not exceed the space provided I 
            
         
            
        Lewis rats and non-human primates, immunized at a site distant to the eye with 
            
        the retinal soluble antigen (S-antigen) in complete Freund's adjuvant, develop 
            
        experimental autoimmune uveitis (EAU) . Lymph node cells and peripheral 
            
        lymphocytes from immunized animals manifested significant cellular imm.une 
            
        responses measured by the lymphocyte culturing technique. Cyclosporine, a drug 
            
        with specific anti-T-activity, has been found to be exceptionally effective in 
            
        protecting rats with EAU, and suppressor cells potentially play a role in this 
            
        protective mechanism. As well, the inducer cell T-cell fraction in the lyir.ph 
            
        node appears to be most susceptible to cyclosporine therapy. Attempts at local 
            
        immunosuppressive therapy in order to prevent EAU have begun. The use of 
            
        topical CsA has been used to evaluate its effectiveness in EAU. Additionally, 
            
        newer cyclosporines, particularly DiG, have been evaluated in this model, with 
            
        their efficacy compared to that of cyclosporine A. Ciamexone, a drug with 
            
        immunopotentiating characteristics, has always been utilized in this model. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl 00115-06 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characters or less Titte must tit on one line between tt>e bonters j 
            
         
            
        Cyclosporine Therapy in Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust othe' pnlessionai personnel below ttie Principal Investigator ) (Name title laboratory ana institute altiiiationi 
            
         
            
        PI: Robert B. Nussenblatt M.D. Deputy Clinical Director 
            
         
            
        NEI 
            
         
            
        Others: Alan G. Palestine M.D. 
            
         
            
        Garth Stevens, Jr. M.D. 
            
         
            
        Leslie S. Fujikawa M.D. 
            
         
            
        Francois Roberge M.D. 
            
         
            
        Richard P. Wetzig M.D. 
            
         
            
        Head, Section on Clinical LI, NEI 
            
         
            
        IniDunology 
            
         
            
        Senior Staff Fellow LI, NEI 
            
         
            
        Senior Staff Fellow LI, NEI 
            
         
            
        Visiting Associate LI, NEI 
            
         
            
        Senior Staff Fellow LI, NEI 
            
         
            
        COOPERATING UNITS (it any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MANYE/\PS 
            
         
            
        52 
            
         
            
        PROFESSIONAL 
            
         
            
        2.52 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        [E (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues 
            
         
            
        G (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standant unreduced type Do not exceed ttte space provided ) 
            
         
            
        Cyclosporine, an endecapeptide fungal product with specific anti-T-cell 
            
        characteristics, will be administered to patients with sight-threatening ocular 
            
        inflammatory disease of non-infectious origin who have failed on either 
            
        corticosteroid or cytotoxic agent therapy. This will be done to test 
            
        cyclosporine 's efficacy in the treatment of uveitis. Within the context of 
            
        these ongoing studies, the effect of hydergine on reversing cyclosporine induced 
            
        nephrotoxicity is being evaluated in a randomized, masked, cross-over study. 
            
        Additionally, selected patients whose uveitis is well controlled on cyclosporine 
            
        for one year or more are undergoing kidney biopsies to evaluate the long term 
            
        effects of this agent. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl n 00159-OA LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30. 1986 
            
         
            
        TITLE OF PROJECT (80 characters <y |»5S Title must lit on one line between the borOers ) 
            
         
            
        Cvclosporine Therapy of Chi l dhood Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust Other prolessionai personnel below the Pnncipa' Inyesligeior ) (Name, title, laboratory ana nstitute filiation) 
            
         
            
        PI: Robert B. Nussenblatt M.D. Deputy Clinical Director 
            
         
            
        NEI 
            
         
            
        Others: Alan G. Palestine 
            
         
            
        Chi-Chao Chan 
            
        William Leake 
            
         
            
        M.D. Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        M.D. Staff Ophthalmologist LI, NEI 
            
         
            
        M.S. Biologist LI. NEI 
            
         
            
        COOPERATING UNITS (H any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.2 
            
         
            
        PROFESSIONAL 
            
         
            
        0.15 
            
         
            
        OTHER 
            
         
            
        0.05 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        E (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues 
            
         
            
        D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanoard unreduced type Do not exceed the space provided ) 
            
         
            
        The efficacy of cyclosporine, an endecepeptide with specific anti-T-cell 
            
        characteristics, is being tested in children with sight-threatening ocular 
            
        inflammatory disease of non-infectious origin who have failed on conventional 
            
        therapy. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00215-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO cffracfn of Uss TitH muti m on off Im* Oatw—t) ttt» bOfOtrs ) 
            
         
            
        Randomized Double-Masked Study of Cyclosporine in Treating Endogenous Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi otner prolessiorai p»r%onn«l twtow rfte Prmc*)*' iriYatligalOf ) (Ntmt rnit laOoftlOfy trta mstnutt ttUhttnn) 
            
         
            
        PI: Robert B. Nussenblatt M.D. Deputy Clinical Director NEI 
            
         
            
        Others: Alan G. Palestine 
            
         
            
        Garth Stevens, Jr. 
            
        Leslie S. Fujikawa 
            
        Chi-Chao Chan 
            
        Richard P. Wetzig 
            
         
            
        M.D. Head, Section on Clinical LI, NEI 
            
         
            
        Immunology 
            
         
            
        M.D. Senior Staff Fellow LI, NEI 
            
         
            
        M.D. Senior Staff Fellow LI, NEI 
            
         
            
        M.D. Staff Ophthalmologist LI, NEI 
            
         
            
        M.D. Senior Staff Fellow LI, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Iramunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
        0.6 
            
         
            
        PROFESSIONAL 
            
         
            
        0.6 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        E (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues Cj (c) Neither 
            
         
            
        SUMMARY OF WORK (Use sianaartl uriraOuced type Do not exceetf tt>e wee proviOea ) 
            
         
            
        Cyclosporine 's efficacy in the treatment of severe endogenous uveitis was 
            
        evaluated in this randomized, double-masked study. The study will evaluate the 
            
        effectiveness of cyclosporine therapy to that of systemic corticosteroid 
            
        administration. Patients meeting the entry requirements were randomized to 
            
        either cyclosporine or corticosteroid therapy. Patients are evaluated at three 
            
        months in order to determine whether they were therapeutic "successes" or not. 
            
        If not, the patients are then treated with the alternate medication. 
            
         
            
        PHS 6040 (Rev 1/84) 
            
         
            
        c»o »l «-«l« 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00228-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (80 characfrs ot Itss TtOt muti lit on on* kn» btlw—n tht borOtrt j 
            
         
            
        Studv of Ocular Glial Cells Involvement in Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usl otttti ptoltstional ptnonntl btlow ttf Prmapsl /nvailva'tv I (Namt. tith. Itortlory, antf niMul* affMbon; 
            
         
            
        PI: Francois Roberge M.D. Visiting Fellow LI, NEI 
            
         
            
        Others: Robert B. Nussenblatt M.D. 
            
        . Chi-Chao Chan M.D. 
            
         
            
        Rachel Caspi Ph.D. 
            
         
            
        Deputy Clinical Director NEI 
            
         
            
        Staff Ophthalmologist LI, NEI 
            
         
            
        Visiting Fellow LI, NEI 
            
         
            
        COOPERATING UNITS f* any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Immunoregulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MANYEARS 
            
         
            
        1.06 
            
         
            
        PROFESSIONAL 
            
         
            
        1.06 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        n (b) Human tissues B (c) Neither 
            
         
            
        SUMMARY OF WORK (L/se sfndtrd unrwiuctO type Do not etcttd tHe space provtOed ) 
            
         
            
        The work concerns uveoretinal inflammatory disease mechanisms. The study 
            
        focused on evaluating the role of resident cells at the target organ level. 
            
        Muller cells interactions with T-lymphocyte cell line was studied in vitro. Two 
            
        opposite effects of Muller cells on T-lymphocytes proliferation were found that 
            
        could be expressed under different culture conditions. An inhibitory effect on 
            
        antigen driven proliferation of T-helper lymphocytes could be modulated with 
            
        various drugs that allowed the Muller cells to function as antigen presenting 
            
        cells . 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00227-01 LI 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (BO cfftcttrz or Its} Tint must In <yi on* *ne bttwttn tht borOtrs ) 
            
         
            
        Histopathology of Pars Planitis and Experimental Autoimmune Uveitis 
            
         
            
        PRINCIPAL INVESTIGATOR fUSI Othtr prottssionti ptrsonnti blow ffM Pn\c^)»l knusUOttot ) (Sunt, MM. IttMrtlory. tnti nsoiult tllJ^tiOn) 
            
         
            
        PI: Richard P. Wetzig M.D. Senior Staff Fellow 
            
         
            
        Others: Robert B. Nussenblatt M.D. 
            
         
            
        Chi-Chao Chan M.D. 
            
         
            
        Barbara Detrick Ph.D. 
            
         
            
        John J. Hooks Ph.D. 
            
         
            
        Deputy Clinical Director 
            
        Staff Ophthalmologist 
            
        Elxpcrt 
            
         
            
        Head, Section on Immunology 
            
        and Virology 
            
         
            
        LI, NEI 
            
         
            
        NEI 
            
        LI, NEI 
            
        LI, NEI 
            
        LI, NEI 
            
         
            
        COOPERATING UNITS (I any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Immunology 
            
         
            
        SECTION 
            
         
            
        Section on Iramunorepulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.67 
            
         
            
        PROFESSKyjAL 
            
         
            
        0.67 
            
         
            
        OTHER. 
            
         
            
        CHECK APPROPRIATE BOXIESI 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        B (b) Human tissues D (c) Neither 
            
         
            
        Summary of work lUse sttnava unrtauctd type Do not eiceecf me ipece provroed ) 
            
         
            
        Studies in animals and in patients are being carried out to determine factors 
            
        influencing ocular immune responses. In an animal model, rats are immunized 
            
        with S-retinal antigen to produce experimental autoimmune uveitis. Animals in 
            
        one group received anti-la antibody intraperitoneally and developed the onset of 
            
        uveitis significantly later and to a lesser extent than controls. Histopatho- 
            
        logically, the anti-la treated animals had much less inflammation than did 
            
        controls. A human eye with pars planitis was also studied immunohistologically . 
            
        In the pars plana region there was an elevated helper to suppressor T-cell 
            
        ratio. In addition, the snowbank area showed staining for glial fibrillary acid 
            
        protein Muller cells, type IV collagen and laminin. There was staining for 
            
        HLA-DR throughout the globe. The results of these studies shed light on how 
            
        surface antigens effect and are transmitted by ocular immune responses. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00201-02 LMOD 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (BO chtrtcxtn or less T/fie tnui\ In o" ont Imt between (fie txyOen ) 
            
         
            
        Molecular Biology of Aldose Reductase 
            
         
            
        PRINCIPAL INVESTIGATOR lUst ofhe' proleniona! personnel beio» trie Principal In^esngticy I (Heme Wit leboreiory ena nswjtt tlliiiiiion) 
            
         
            
        PI: Deborah Carper 
            
         
            
        Others:' Toshimichi Shinohara 
            
        Cheryl Craft 
            
        Jin H. Kinoshita 
            
         
            
        Ph.D. Biologist 
            
         
            
        Ph.D. Biologist 
            
         
            
        Ph.D. Guest Worker 
            
         
            
        Ph.D. Scientific Director 
            
         
            
        LMOD, NEI 
            
         
            
        LMDB, NEI 
            
         
            
        MIDP, NICHHD 
            
        NEI 
            
         
            
        COOPERATING UNITS (it tny) 
            
         
            
        None 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Disease 
            
         
            
        SECTION 
            
         
            
        Section on Cataracts 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH. Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        1 .2 
            
         
            
        PROFESSIONAL 
            
         
            
        1 .2 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        C (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        C (b) Human tissues C (c) Neither 
            
         
            
        SUMMARY OF WORK (Uie stenOara unreauce<i type Do oof exceed tfie space proviOeO ) 
            
         
            
        Aldose reductase (AR), an enzyme which converts sugars to sugar alcohols, has 
            
        been implicated in diabetic complications of the eye and the peripheral nerves. 
            
        Our studies have focused on Isolating and characterizing the gene for aldose 
            
        reductase. As an initial step, putative AR cDNA clones from a bovine retina cDNA 
            
        Agt 11 library were Isolated and sequenced. Sequencing of three non-homologous 
            
        inserts yielded approximately 700 nucleotides or around one-third of the full 
            
        length mRNA. Northern analysis showed that the full size of AR mRNA is around 2 
            
        kilobases in the bovine retina and slightly larger in the bovine brain. 
            
        Homologies between the bovine retina AR cDNA and mRNAs from cultured dog lens 
            
        epithelial cells and cultured rabbit kidney cells have not been detected. 
            
        Restriction enzyme analysis xif total bovine genomic DNA indicates that fewer than 
            
        3 genes are present. 
            
         
            
        DEPARTMENT Or HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        SOI EY 00235-01 LMOD 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE Of PROJECT (80 cfrtcnrj or tfss Tin* muJi fK or one *o» bttwten me borotrs ) 
            
         
            
        Philly Mouse Cataract 
            
         
            
        PRINCIPAL INVESTIGATOR (Lai otn»' proitisiona' ptr^onnei btio* rtte Pnncipai invtstigalo' I (Name me luborttory ena ntmute etfihationi 
            
         
            
        PI: Deborah Carper Ph.D. 
            
         
            
        Others: George Inana M.D., Ph.D, 
            
        Jin H. Kinoshita Ph.D. 
            
         
            
        Biologist 
            
         
            
        LMOD, NEI 
            
         
            
        Medical Officer LMOD, NEI 
            
        Scientific Director NEI 
            
         
            
        COOPERATING UNrrS (I* eny) 
            
         
            
        John Clark Ph.D., faculty University of Washington School of Medicine 
            
        Mike Gorin M.D., Ph.D. UCLA School of Medicine 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Disease 
            
         
            
        SECTION 
            
         
            
        Section on Cataracts 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH. Bethesda. Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
        0.2 
            
         
            
        PROFESSIONAL 
            
         
            
        0.2 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOXIESI 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        G (a2) Interviews 
            
         
            
        D (b) Human tissues E (c) Neither 
            
         
            
        SUMMARY Of WORK (Uie ttanoara unreOuced rype Do not etceeO f>e space provioea ) 
            
         
            
        Studies are continuing on the Philly mouse which develops a dominantly inherited 
            
        cataract. The cataract is visible by 35 days of age. Microscopic changes in the 
            
        lens occur much earlier and include failure of lens fiber cells to elongate. We 
            
        have been investigating several facets of cataract development in the Philly 
            
        mouse including the composition of crystallin proteins at different stages in 
            
        lens growth, synthesis and translational efficiencies of lens mRNAs, and phase 
            
        transition temperatures in the Philly mouse and Fi heterozygote. 
            
         
            
        2-D gel electrophoresis of Philly mouse lens proteins indicate a specific 
            
        deficiency of a 27K basic :-crystallin and its functional mRNA. Interestingly, a 
            
        unique more acidic 26K protein and its functional mRNA is present. The relation- 
            
        ship between these two proteins is now being investigated using a ;Bp cDNA probe. 
            
         
            
        The behavior of the lens cytoplasm phase transition temperature (Tc) was differ- 
            
        ent in the Swiss-Webster, Philly, and Swiss Webster x Philly heterozygotes . The 
            
        slope (dTc/dt) changes from negative to positive on day 27 for the Philly and day 
            
        38 for the hybrid, just prior to cataract in these animals. The slope continues 
            
        to be negative in the Swiss Webster. The change in slope is a graphical confir- 
            
        mation of the disturbance in lens cell composition and an early indicator of 
            
        conditions which lead to opacity. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
         
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER I 
            
         
            
        Z01 EY 00189-03 LMOD 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characlars or less Titit must til on one lin« ttttwetn tfte (xyMrj ) 
            
         
            
        Protein Kinases in Lens Function and Oxidation of Proteins in Cataractogenesis 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi Other prol0ssionai parsoitnei below Itte Prmcipei In^sngaior > (Name mie laooralory. ana natituie atfihationj 
            
         
            
        Donita L. Garland Ph.D Expert LMOD, NEI 
            
         
            
        COOPERATING UNITS (It any) 
            
         
            
        None 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Disease 
            
         
            
        SECTION 
            
         
            
        Section on Cataracts 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
        1.0 
            
         
            
        PROFESSIONAL 
            
         
            
        1.0 
            
         
            
        OTHER 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        □ (a1) Minors 
            
        G (a2) Interviews 
            
         
            
        5 (b) Human tissues D (c) Neither 
            
         
            
        Summary of work fUse stanoam unreaucea type Do not etceeti the space proviOeO I 
            
         
            
        The role of protein kinases in regulating metabolism in lens is being 
            
        addressed by studying: 1) the protein kinases, and 2) the endogenous proteins 
            
        that serve as substrates for the lens protein kinases. The focus of this study 
            
        is on the purification of the protein kinases and the characterization of the 
            
        phosphorylation of four endogenous substrates by cAMP-dependent protein kinases. 
            
        The phosphorylated proteins are a-crystallin and 26K and 19K intrinsic membrane 
            
        proteins. Comparison of the amino acid compositions of the 26K and 1 9K proteins 
            
        suggest they are closely related. Detailed structural studies are in progress to 
            
        determine how similar they are. Compounds that are thought to regulate the 
            
        function of the 26K protein in vivo modulate the phosphorylation of the protein 
            
        in vitro. 
            
         
            
        Oxidative changes of lens proteins are thought to occur with aging and 
            
        to contribute to the development of cataracts. The goals of this project are to 
            
        determine: 1) the extent of oxidative modification of crystallins and metabolic 
            
        enzymes in both normal and cataractous lenses; 2) the nature of the modifications 
            
        and mechanisms leading to the changes; 3) the effect of the modifications on 
            
        structure and function of lens protein. Bovine and human lenses were used. 
            
        Incubation of crystallins with ascorbate - FeCl3-02 caused nondisulflde 
            
        crosslinking of a and B and the partial degradation of all 3 crystallin frac- 
            
        tions. Conversion to more acidic species occurred with all 3 fractions, and 
            
        nontryptophan fluorescence was produced in 6h fraction. Longer incubations of 
            
        homogenate with ascorbate - Fe-02 mimicked changes similar to those in brunescent 
            
        lenses. Proteins became brownish, insoluble and there was an increased carbonyl 
            
        content. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00237-01 LMOD 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO cnt'icieri c lesi Tdle must lit or one lint between me OOTJe'S ) 
            
         
            
        Characterization of the Primate Lens 
            
         
            
        PRINCIPAL INVESTIGATOR (List ofw prolessionai personnel below the Pnncipe: InvestigaiO' ) (Name title, laboritory ana msWutt atlihat'Oni 
            
         
            
        PI: Paul Russell Ph.D. Research Chemist LMOD, NEI 
            
         
            
        COOPERATING UNITS (// any) 
            
         
            
        LAB'BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Diseases 
            
         
            
        SECTION 
            
         
            
        Section on Cataracts 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        1.0 
            
         
            
        PROFESSIONAL 
            
         
            
        1.0 
            
         
            
        OTHER 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        E (b) Human tissues D (c) Neither 
            
         
            
        Summary of work (Use sianaara unreoucea fype Do nor eJTceea the space proviOeO ) 
            
         
            
        Developmental differ 
            
        with both monkey and 
            
        to those observed in 
            
        investigate the role 
            
        crystallin proteins 
            
        cells have been stud 
            
        indication of factor 
            
        crystallins may also 
            
         
            
        ences in the composition of lens proteins have been observed 
            
        human lenses. These alterations in composition were similar 
            
        rodent lenses at similar stages in development. In order to 
            
        in which these changes may affect optical clarity, the lens 
            
        as well as the glycoproteins from the membrane of the lens 
            
        ied. Differences in the crystallin composition may give an 
            
        s involved in congenital cataracts. Changes in individual 
            
        be important to understand the aging process in the lens. 
            
         
            
        6- and y- crystallin compositions are changing in 
            
        the primate lens. The 6-crystallins have much hi 
            
        in the fetal lens perhaps indicative of a differe 
            
        of these proteins during this stage of developmen 
            
        Y-crystallin in the embryonic lens is only a very 
            
        lens. As the lens cells differentiate into fiber 
            
        composition on their membranes changes. Specific 
            
        been seen In cataractous rodent lenses compared w 
            
        lectins, primate lenses can now be probed for cha 
            
        formation and development. 
            
         
            
        the early embryonic period of 
            
         
            
        gher apparent molecular weights 
            
        nt organization of the subunits 
            
        t. In addition, the main 
            
        minor component in the adult 
            
        cells, the glycoprotein 
            
        glycoprotein differences have 
            
        ith normal lens; and using 
            
        nges related to cataract 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00105-07 LMOD 
            
         
            
        PERlOP COVERED 
            
         
            
        DctoBer 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 cntrBCttrs or Itss Tit<t musr tn on on* hot MrwMi p>» borMrsj ^ 
            
         
            
        Structure and Composition of Lens Crystallins with Respect to Cataractogenesis 
            
         
            
        PRINCIPAL INVESTIGATOR /'Ljs: olfte- prqttss^onf perjonnf btvo ff>e Pnncip*' In^siigtio- > (V»'n* w* l*txfr»tory tna nsinjJt •f>/i»f>on; 
            
         
            
        PI: J. Samuel Zigler, Jr. Ph.D. Researcn Biologist LMOD, NEI 
            
         
            
        Others: Valerie A. Lucas 
            
        • Qing-ling Huang 
            
         
            
        Ph.D. Visiting Fellow 
            
         
            
        M.D. Visiting Fellow 
            
         
            
        LMOD, NEI 
            
        LMOD, NEI 
            
         
            
        COOPERATING UNITS (if inyi 
            
         
            
        Jules stein Eye institute, UCLA Medical School (J. Horwitz); Department of Chemistry, 
            
        Adelphi University (F. Bettelheim); Department of Ophthalmology, University of 
            
        .Tennessee (H.M. Jernigan) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Diseases 
            
         
            
        SECTION 
            
         
            
        Section on Cataract 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN YEARS 
            
         
            
        2.8 
            
         
            
        PROFESSIONAL 
            
         
            
        2.8 
            
         
            
        OTHER 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        C (a) Human subjects 
            
        lZ (a1) Minors 
            
        G (a2) Interviews 
            
         
            
        E (b) Human tissues C (c) Neither 
            
         
            
        SUMMARY o^ WORK (Use sunaa'O jnreducta type Do not eiceeo rne ipace pro^iaeti ) 
            
         
            
        The ocular lens normally exists in an environment of high oxidative stress which ■ 
            
        is manifested in the occurrence of marked oxidative modification to lens proteins 
            
        during aging and particularly during cataract development. We are engaged in 
            
        characterizing such protein changes and elucidating the mechanisms which produce 
            
        them. Model systems are used to study changes produced in organ cultured lenses 
            
        or in crystallin solutions. Complex interactions among the various forms of 
            
        activated oxygen are involved in the damage produced in such model systems and 
            
        very probably in the lens in vivo as well. The potential of the various 
            
        activated oxygen species to produce damage depends upon where they are generated, 
            
        ie, inside the lens or in the external milieu. Understanding the interactions 
            
        among the oxidant species and lens components is essential if we are to devise 
            
        therapeutic means to prevent oxidative damage. 
            
         
            
        The study of animal colonies with hereditary cataract has provided numerous 
            
        insights into processes of cataractogenesis. We have begun to investigate the 
            
        nuclear cataracts present congenitally in a colony of guinea pigs. Dr. Q-L. 
            
        Huang has isolated and described the crystallins from normal guinea pigs so that 
            
        they can be compared with crystallins from the cataractous animals. The 
            
        discovery of a new crystallin not present in other species raises exciting 
            
        possibilities for study of gene expression in the lens. 
            
         
            
        Transport processes are vital to the maintenance of normal lens homeostasis. Dr. 
            
        V.A. Lucas is studying the membrane protein present in lens which transports 
            
        glucose across cell membranes. This glucose transporter has been isolated and an 
            
        antibody raised against it. Characterization of glucose transport in monkey 
            
        lens membranes has been done using specific binding assays and known inhibitors 
            
        of the glucose transporter. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00193-03 LMOD 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characltrz or less Titte most tit on ooe Ime Derw««n iht borOtrs I 
            
         
            
        Molecular Biology of Hereditary Eye Diseases 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi oth«r prolasiionH p»nonntl twtow me Pnncipti InvasligatO' ) (Nama bile. ItOoratory. ana mstiti/la alliiiation) 
            
         
            
        PI: George Inana M.D., Ph.D. Section Head LMOD, NEI 
            
         
            
        Others: Seiichi Totsuka M.D., 
            
         
            
        Carmelann Zintz Ph.D. 
            
         
            
        Yoshihiro Hotta M.D. 
            
         
            
        T, Michael Redmond Ph.D. 
            
         
            
        Ph.D. Visiting Fellow LMOD, NEI 
            
         
            
        Staff Fellow LMOD, NEI 
            
         
            
        Visiting Fellow LMOD, NEI 
            
         
            
        Staff Fellow LRCMB, NEI 
            
         
            
        COOPERATING UNITS (it any) 
            
         
            
        See next page. 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Diseases 
            
         
            
        SECTION 
            
         
            
        Molecular Pathology Section 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda. MD 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        3.6 
            
         
            
        PROFESSIONAL 
            
         
            
        3.6 
            
         
            
        OTHER: 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        E (b) Hunnan tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use slanaarO unreCuced type Do not B*co«d ffte space provided ) 
            
         
            
        Ornithine Aminotransferase Deficiency in Gyrate Atrophy: Gyrate atrophy (GA) is 
            
        an autosomal recessive degenerative disease of the retina and choroid of the eye 
            
        which leads to blindness. We have isolated a gene probe for the human ornithine 
            
        aminotransferase (OAT), a mitochondrial enzyme which is deficient in GA patients. 
            
        The gene probe is a Xgtll cDNA clone which was obtained from our human cDNA librarj 
            
        through a Western screening method using the anti-human OAT antibodies. The OAT 
            
        cDNA is 2073 base pairs long and contains the complete coding sequence of the 
            
        protein. The cDNA-derived OAT sequence is a precursor containing a leader sequence 
            
        like other mitochondrial enzymes, matches the sequences of seven purified tryptic 
            
        peptides of pure OAT, and shows homology with another mitochondrial enzyme, 
            
        aspartate aminotransferase. Examination of the genomic organization of OAT using 
            
        the cDNA as a probe revealed a gene family consisting of approximately four copies 
            
        of OAT or OAT-like gene sequences. The OAT gene sequences were mapped to multiple 
            
        chromosomal loci, confirming the presence of a gene family. Examination of the OAT 
            
        genes of GA patients has revealed restriction fragment length polymorphisms but no 
            
        grossly obvious abnormalities, Including deletions. Characterizations of multiple 
            
        gene clones of OAT and the status of OAT mRNA synthesis in GA patients are in 
            
        progress. 
            
         
            
        Hereditary Retinoblastoma: We are investigating the molecular basis of malignant 
            
        transformation in hereditary retinoblastoma using cell culture and molecular 
            
        genetic techniques. To determine if retinoblastoma has a dominant or recessive 
            
        malignant phenotype, retinoblastoma cells (Y79) were fused with non-malignant cells 
            
        (NIH3T3), and the growth characteristics of the hybrid cells were studied. The 
            
        hybrid cells, containing both the neomycin and GPT markers from the parents, are 
            
        anchorage-dependent, have a fibroblastic morphology and do not grow in soft agar 
            
        like the non-malignant parent. The results indicate the malignant phenotype of 
            
        retinohlastoma tn Hp rPPP.^^gi vp . 
            
         
            
        I PROJECT NUMBER 
            
         
            
        J01 EY 00003-1 'J LMOD 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 ctiaraclgrs or less Title must tit on one line between tr>e bortlen ) 
            
         
            
        Pharmacology of Ocular Complications 
            
         
            
        PRINCIPAL INVESTIGATOR (Utl otrier pnlessionn personnel Oeto* the Pnncipei Investigaior ) (Name, title laboratory, ana nstiti/te aHiiiai>oni 
            
         
            
        PI: Peter F. Kador Ph.D. Research Chemist LMOD, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        None 
            
         
            
        LAB'BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Diseases 
            
         
            
        SECTION 
            
         
            
        Section on Molecular Pharmacology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        PROFESSIONAL 
            
         
            
        3.3 
            
         
            
        2.8 
            
         
            
        OTHER 
            
         
            
        0.5 
            
         
            
        CHECK APPROPRIATE BOX(ESl 
            
         
            
        D (a) Human subjects 
            
        C (a1) Minors 
            
        D {a2) Interviews 
            
         
            
        C (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standard unreduced type Do not eiceed f>e space provided ) 
            
         
            
        Studies are being conducted on events leading to the onset of various ocular 
            
        diseases and on methods for their potential pharmacological control. The 
            
        relationships between the enzymes aldose reductase and aldehyde reductase and the 
            
        progression of ocular complications such as retinopathy, cataract, pupil function 
            
        and iris changes, and keratopathy induced by diabetes or galactosemia are being 
            
        investigated. Methods for either delaying or preventing the onset of these 
            
        complications through the pharmacological control of aldose reductase are also 
            
        being developed. 
            
         
            
        Events leading to the formation of several types of cataracts are also being 
            
        studied as well as methods for controlling the onset of these cataracts through 
            
        pharmacological intervention. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY OOT<9-13 LMOD 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (8C cftartcifrz ly l»si f»f<e musi lit or one Imt twrween mt bontri ) 
            
         
            
        Ultrastructure and Function of the Cells and Tissues of the Eye 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi ointi proltisiona! ptrtonnti baio» m# Principal In^stigato' ) (Namt mi* latxyaiiyy arte niuiiAt aHihaiior}/ 
            
         
            
        PI: W. Gerald Robison, Jr. Ph.D. 
            
         
            
        Othersr' Martin L. Katz Ph.D. 
            
         
            
        Masao Nagata M.D. , 
            
         
            
        Thomas C. Hohman Ph.D. 
            
         
            
        Ph.D. 
            
         
            
        Chief, Section on 
            
        Pathophysiology 
            
         
            
        Staff Fellow 
            
        Visiting Associate 
            
        Senior Staff Fellow 
            
         
            
        LMOD, NEI 
            
         
            
        LMOD, NEI 
            
        LMOD, NEI 
            
        LMOD, NEI 
            
         
            
        COOPERATING UNITS <il any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Mechanisms of Ocular Diseases 
            
         
            
        SECTION 
            
         
            
        Section on Pathophysiology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        5.2 
            
         
            
        PROFESSIONAL 
            
         
            
        5.0 
            
         
            
        OTHER 
            
         
            
        .2 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (al) Minors 
            
        D (a2) Interviews 
            
         
            
        (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use star\aarrJ unrtaucea type Do nor atcaoa the space proviOee ) 
            
         
            
        Aldose reductase has been implicated in two histopathological hallmarks of 
            
        diabetic retinopathy involving retinal capillary walls: 1) the selective loss in 
            
        numbers of mural cells (intramural pericytes) from the capillaries; and 2) the 
            
        thickening of the basement membranes which envelop the cells of the capillary 
            
        walls. Mural cells contain aldose reductase, accumulate sorbitol, and appear to 
            
        be more susceptible to incubation in high glucose than are endothelial cells. A 
            
        thickening of capillary basement membrane ultrastructurally similar to that 
            
        characteristic of diabetic retinopathy was induced in rat retinas by galactose 
            
        feeding and was prevented by two structurally different inhibitors of aldose 
            
        reductase. The diabetic-like thickening of retinal capillary basement membranes 
            
        in galactose-fed rats was accompanied by other ultrastructural alterations 
            
        mimicking changes typical of diabetic microangiopathy, such as multilamination, 
            
        banding of collagen, and the formation of vacuoles and dense inclusions. Bovine, 
            
        canine, and human mural cells and endothelial cells from retinal capillaries have 
            
        been grown in cell culture so that the role of aldose reductase in basement 
            
        membrane synthesis and in various complications of the diabetic state could be 
            
        studied under chemically defined conditions. Aldose reductase inhibitors are 
            
        useful for studies of the possible prevention of diabetic retinopathy by oral 
            
        drugs. 
            
         
            
        ANNUAL REPORT 
            
         
            
        NATIONAL EYE INSTITUTE 
            
         
            
        October 1, 1985 - September 30, 1986 
            
         
            
        REPORT OF THE CHIEF, LABORATORY OF MOLECULAR AND 
            
         
            
        DEVELOPMENTAL BIOLOGY 
            
         
            
        Joram Piatigorsky, Ph.D. 
            
         
            
        This is the fifth year for the Laboratory of Molecular and Developmental 
            
        Biology. The three Sections (established in FY 1986) have established autonomy 
            
        while remaining integrated in their life-styles and their common efforts to 
            
        study the visual system at the molecular level. The Thursday morning 
            
        doughnut-data sessions have continued to keep everyone abreast of on-going work 
            
        cind use the collective knowledge of the laboratory members. The invited 
            
        seminars on alternate Tuesdays was organized this year by Dr. Teresa Borras and 
            
        featured a stimulating series of talks, while our Journal club on the other 
            
        Tuesdays continued to keep us informed on recent developments in this rapidly 
            
        moving area of science. 
            
         
            
        Each Section made notable gains in their research this year, as indicated 
            
        in the individual reports given in this volume. Some of the recent progress 
            
        includes not just new findings but reflects a growing clarity in direction. 
            
        For example, while my group continues to characterize the structure and 
            
        organization of crystallin genes — ie, to clone and sequence — we have advanced 
            
        our efforts to include function. Crystallin gene promoters are being studied 
            
        simultaneously in cell-free systems, in cultured cells and in transgenic mice. 
            
        Each approach has its advantages and pitfalls. By combining the methods we 
            
        hope to active a deeper understanding of the regulated, tissue-specific nature 
            
        of crystallin gene expression. Acquisition of an oligonucleotide synthesizer 
            
        has also had an Impact on our work in that we can now make mutations in cloned 
            
        gene sequences more easily and cheaply. Despite the considerable expenses of 
            
        this equipment, it has already paid for itself and been of use to several 
            
        laboratories in the NEI and other institutes. 
            
         
            
        In addition to continuing to study the metabolic control of lens cell 
            
        growth and differentiation, Dr. Peggy Zelenka's section has been increasingly 
            
        incorporating molecular genetics in their work. Their initial finding reported 
            
        last year that the oncogene mRNA c-myc is transiently increased during lens 
            
        fiber cell differentiation has been developed and expanded to other oncogenes. 
            
        They have found that several oncogenes are expressed in the developing lens, 
            
        each with a characteristic pattern during differentiation. The role of the 
            
        oncogene products in the lens is not known yet, but the combined approach of 
            
        nDolecular and biochemical investigations should yield new insights to the 
            
        regulation of lens cell growth and differentiation. 
            
         
            
        Last year Dr. Toshimlchi Shlnohara's group reported their initial studies 
            
        on S-antigen of the retina. They identified several cDNA clones as S-antigen 
            
        and begun in situ hybridization experiments on the localization of opsin and 
            
        S-antigen raRNAs in the retina and pineal gland. This year Dr. Shlnohara's 
            
        group has obtained considerably more sequence information on S-antigen and 
            
        isolated S-antigen genes from the mouse and human, opening new possibilities 
            
        for the study of tissue-specific gene expression in the retina. Growing 
            
        knowledge of the sequence of S-antigen has permitted the synthesis of peptides 
            
         
            
        of S-antigen. These, in tarn, are being used to define sites of S-antigen 
            
        which are responsible for the generation of uveitis in experimental rats. 
            
        Thus, Dr. Shinohara's basic investigations are being pr-oductlvely coupled with 
            
        studies having direct relevance to medicine. 
            
         
            
        In FY 1985 we began a very fruitful collaboration with Dr. Heiner Westphal 
            
        and his colleagues in the Laboratory of Molecular Genetics (NICHD) for testing 
            
        crystallin promoters in transgenic mice. These studies have now demonstrated 
            
        the extreme tissue-specificity of the murine uA-crystallin promoter and its 
            
        ability to regulate foreign genes (bacterial and viral) in transgenic mice. In 
            
        one case, transgenic mice were made which contained the aA-crystallin promoter 
            
        fused to the T-antigen gene of SVi<0. The lenses of these mice were 
            
        neoplastically transformed, showing for the first time that the lens is not 
            
        refractive to cancer, as was long believed. More importantly, the transgenic 
            
        mice experiments established that crystallin promoters can be used to modify 
            
        lens genotype and phenotype by genetic engineering. In addition, our results 
            
        suggest strongly that regulatory sequences for other genes, for example 
            
        S-antigen or opsin which are expressed in the retina, can also be used to 
            
        direct foreign genes to different ocular tissues. Thus, it has become possible 
            
        to consider genetic engineering for both basic and potentially clinical 
            
        investigations on the eye. We are in the process of developing a facility to 
            
        produce transgenic mice in our laboratory. Dr. Ana Chepelinsky has been 
            
        very much involved in this effort. Hopefully, FY 1987 will witness the birth 
            
        of many interesting LMDB transgenic mice. 
            
         
            
        Finally, the ARVO electorate has been kind to us this year. Dr. Peggy 
            
        Zelenka has been elected to the program committee (1987-1939) of the Lens 
            
        Section and I have been elected as a trustee (1986-1990) representing the Lens 
            
        Section. This will give the LMDB an administrative voice contributing to the 
            
        advancement of vision research. Numerous collaborations with other 
            
        laboratories (listed in the individual reports) have expanded our scope of 
            
        research and are much appreciated. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00127-10 LMDB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characters or less Title must lit on one Ime between the tx>raers > 
            
         
            
        Plasma Membrane Composition and Biosynthesis in Chick Lens Fibers and Epithelia 
            
         
            
        PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator ) (Name title laboraior}. ana mstitute altiiiation) 
            
         
            
        PI: Peggy Zelenka Ph.D. Geneticist LMDB, NEI 
            
         
            
        Luke Pallansch 
            
        Malini Vatal 
            
        Jodell Boyle 
            
         
            
        Ph.D. Staff Fellow 
            
        Ph.D. Visiting Fellow 
            
        B.S. Medical Student 
            
         
            
        LMDB, NEI 
            
        LMDB, NEI 
            
         
            
        HHMI 
            
         
            
        COOPERATING UNITS it' any) 
            
         
            
        Beltsville Agricultural Research Center, Betlsville, MD (A. Ferretti) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Molecular and Development Biology 
            
         
            
        SECTION 
            
         
            
        Section on Cellular Differentiation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        2.3 
            
         
            
        PROFESSIONAL 
            
         
            
        1.5 
            
         
            
        OTHER 
            
         
            
        0.8 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        C (al) Minors 
            
        D (a2) Interviews 
            
         
            
        n (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanaara unreduced type Do not exceed the space provided ) 
            
         
            
        This project seeks to determine whether the regulation of lens fiber 
            
        differentiation and maturation is associated with alterations in the plasma 
            
        membrane. The composition, biosynthesis, and metabolism of lens lipids have 
            
        been investigated using embryonic and adult chicken lenses, and cultured lens 
            
        epithelial cells derived from the Nakano mouse. The rate of degradation of the 
            
        membrane phospholipid, phosphatidylinositol, has been shown to be tightly 
            
        coupled to the rate of lens epithelial cell division and to cease when the 
            
        epithelial cells differentiate to form lens fibers. Cultured lens epithelial 
            
        cells and cultured fibroblasts have been shown to possess a mechanism for the 
            
        rapid, transient gradation of phosphatidylinositol, which is independent of 
            
        phospholipase C or phospholipase A2. A similar pathway may play a role in the 
            
        differentiation of lens epithelial cells into lens fibers. Since 
            
        phosphatidylinositol is rich in arachldonic acid, a precursor of prostaglandins 
            
        and leukotrienes, the metabolities of arachidonic acid produced by lens 
            
        epithelial cells are being characterized in an effort to understand the 
            
        physiological role of phosphatidylinositol degradation. Analysis of the 
            
        archadonic acid metabolities of cultured lens epithelial cells of several 
            
        species revealed the presence of both cyclo-oxygenase and lipoxygenase 
            
        products, including prostagladlns E2 and F2a, and leukotrienes. All lens 
            
        epithelial cell types examined synthesized products of the S-lipoxygenase 
            
        pathway of arachidonic acid metabolism. One product of this pathway, 
            
        5-hydroxytetraenolc acid, was weakly mltogenlc when added to cultured lens 
            
        epithelial cells in the absence of serum or growth factors. Alterations in 
            
        phosphatidylinositol metabolism and in the production of arachidonic acid 
            
        fiietabolities are being correlated with the action of growth factors in 
            
        regulating cell division and differentiation. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00238-01 LMDB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 cttaracieri ot lesi Title must til on one lint between tf>e borders I 
            
         
            
        Proto-oncogene Expression During Lens Differentiation and Development 
            
         
            
        PRINCIPAL INVESTIGATOR iLisi otfiei proteinonal personnel belo* the Pnncipei Investigato' ) (Heme title leboretory •no msiitute etfiiiilion) 
            
         
            
        PI: Peggy Zelenka Ph.D. Geneticist LMDB, NEI 
            
         
            
        Others: 
            
         
            
        Luke Pallansch 
            
        Malini Vatal 
            
        Pravendra Nath 
            
         
            
        Ph.D. Staff Fellow 
            
        Ph.D. Visiting Fellow 
            
        Ph.D. Visiting Fellow 
            
         
            
        LMDB, NEI 
            
        LMDB, NEI 
            
        LMDB, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        David C. Beebe 
            
         
            
        Ph.D. Uniformed Services University 
            
        of the Health Sciences 
            
        Bethesda, MD 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Molecular and Developmental Biology 
            
         
            
        SECTION 
            
         
            
        Section on Cellular Differentiation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        2.0 
            
         
            
        PROFESSIONAL 
            
         
            
        1.7 
            
         
            
        OTHER 
            
         
            
        0.3 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        G (a1) Minors 
            
        G (a2) Interviews 
            
         
            
        Q (b) Human tissues G (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanaarO unreducea type Do not sxceeo tne space provioea ) 
            
         
            
        This project investigates th 
            
        differentiation of embryonic 
            
        and seeks to determine the s 
            
        in the developing lens. Usi 
            
        that mRNA levels for two pro 
            
        regulated during the differe 
            
        form lens fiber cells, both 
            
        transiently elevated during 
            
        differentiation in vitro, as 
            
        cycle. Since the c-myc gene 
            
        transient elevation of c-myc 
            
        regulation of other, differe 
            
        more slowly than levels of c 
            
        embryonic fiber cells. The 
            
        kinase, the substrates of wh 
            
        developing embryonic chicken 
            
         
            
        e expression of proto-oncogenes during the 
            
         
            
        lens epithelial cells to form lens fiber cells, 
            
        pecific function of the corresponding gene products 
            
        ng radioactivity labeled DNA probes we have shown 
            
        to-oncogenes, c-myc and c-src, are specifically 
            
        ntiation of chicken embryo lens epithelial cells to 
            
        in vivo and in vitro. Levels of c-myc mRNA are 
            
        the first few hours after the initiation of 
            
        the differentiating cells withdraw from the cell 
            
        product is a nuclear, DNA-binding protein, the 
            
        mRNA in differentiating lens cells may lead to the 
            
        ntiation-specif ic genes. Levels of c-src mRNA rise 
            
        -myc mRNA, and remain elevated in the mon-dividing 
            
        c-src gene product is a tyrosine-specif ic protein 
            
        ich we are presently investigating in the 
            
        lens. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00132-05 LMDB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 characlarz o' less Title must tit on ont lint £>etw»on tht bonjtrs ) 
            
         
            
        Molecular Biology of Photopigments 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi othtr pnltisionai personnel below the Principal Investigato' ) (Name title. laPoraiory ana mstitule aHikationi 
            
         
            
        PI: Toshimichi Shlnohara Ph.D. Head LMDB, NEI 
            
         
            
        Others: 
            
         
            
        Graeme Wistow 
            
        Albine Katial 
            
        Cheryl Craft 
            
        Masahiko Tsuda 
            
        Theo Van Veen 
            
         
            
        Ph.D. 
            
         
            
        Ph.D. 
            
        Ph.D. 
            
        M.D., 
            
        Ph.D. 
            
         
            
        Ph.D. 
            
         
            
        Visiting Fellow 
            
        Staff Fellow 
            
        Guest Worker 
            
        Visiting Fellow 
            
        Guest Worker 
            
         
            
        LMDB, NEI 
            
        LMDB, NEI 
            
        LDN, NICHD 
            
        LMDB, NEI 
            
        LRCMB, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        See next page 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Molecular and Developmental Biology 
            
         
            
        SECTION 
            
         
            
        Section on Molecular Biology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        l.^ 
            
         
            
        PROFESSIONAL 
            
         
            
        OTHER 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Uie stanaara unrwluced type Do not exceea the space ptovK)e<3 ) 
            
         
            
        We have examined the structure, function, development evolution, epitopes 
            
        and uveitogenic site of the retinal S-antigen (^8k protein). The cDNAs of 
            
        S-antigen have been isolated from bovine retina libraries and their DNA 
            
        sequences have been determined. The predicted amino acid sequence was matched 
            
        completely with that of S-antigen determined by Edman degradation method. 
            
        S-antigen polypeptide has some sequence homologies with Ga-transducin including 
            
        the cholera toxin, pertussis toxin and enterotoxin ADP-ribosylation sites and 
            
        purine nucleotide-binding sites. S-antigen is found to be a glycoprotein and 
            
        its sugar moeity is glucose and mannose. Secondary structure prediction and 
            
        circular dichroism analysis indicated that S-antigen has a predominantly 
            
        extended (6-sheet) structure with a small C-terminal helical region. The 
            
        location of the two monoclonal antibodies binding sites and the one uveitogenic 
            
        site of S-antigen has been detennined. These three linear immunogenic sites 
            
        were localized within 20 amino acid residues at three separated sites. The 
            
        mRNA of S-antigen is approximately 2 kb long and present in the rod cells but 
            
        not present in the majority of cone cells. The majority of mfiNA was found 
            
        very close to the nucleus but not found in the most part of myoid and ellipoid 
            
        of the rod inner segments. Also S-antigen mRNA was present in certain types of 
            
        pinealocytes. S-antigen has only one gene in mouse and human. Indicating that 
            
        the S-antigen of retina and pineal is the same. The S-antigen genes of human 
            
        and mouse were isolated and identified by partial DNA sequences and the human 
            
        S-antlgen gene is located on the chromosome No. l^J . 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00126-05 UOB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO characltrz or Itit Title must In on one line between ttte boraers ) 
            
         
            
        Crystallln Genes: Structure, Organization, Expression, and Evolution 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust ottie' p'o/ess>on«' personnel below the Principal Investigator i (Name title laboratory ana institute alfiiialion) 
            
         
            
        PI: Joram Piatigorsky Ph.D. Chief LMDB, NEI 
            
         
            
        Ana B. Chepelinsky Ph.D. 
            
         
            
        Graeme J. Wistow Ph.D. 
            
         
            
        John F. Klement Ph.D. 
            
         
            
        Mark A. Thompson Ph.D. 
            
         
            
        Charlotte A. Peterson Ph.D. 
            
         
            
        Eric F. Wawrousek Ph.D. 
            
         
            
        Expert 
            
         
            
        Visiting Associate 
            
        Staff Fellow 
            
        Staff Fellow 
            
        Guest Worker 
            
        Staff Fellow 
            
         
            
        LMDB, NEI 
            
         
            
        LMDB, NEI 
            
         
            
        LMDB, NEI 
            
         
            
        LMDB, NEI 
            
         
            
        LMDB, NEI 
            
         
            
        LMDB, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        See next page. 
            
         
            
        LAB/B RANCH 
            
         
            
        Laboratory of Molecular and Developmental Biolgy 
            
         
            
        SECTION 
            
         
            
        Section on Molecular Genetics 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        13.0 
            
         
            
        PROFESSIONAL 
            
         
            
        13.0 
            
         
            
        OTHER 
            
         
            
        I 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        G (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues 
            
         
            
        (c) Neither 
            
         
            
        SUMMARY OF WORK {Use standard unreduced type Do not exceed the space PT)w/0e<3 ) 
            
         
            
        We have continued to characterize the structure, expression and evolution 
            
        of crystallin genes of the eye lens. Sequences have been obtained for the 
            
        6B1-, 6A3/A1- and 62-crystallin chicken cDNAs. Gene sequences have been 
            
        derived for chicken and human oA-crystallin chicken BBI- and eA3/A1-crystallin, 
            
        and chicken 6-crystallin. Both chicken 6-crystallin polypeptides were shown to 
            
        be generated from the 61 mRNA by a translational or co-translational mechanism. 
            
        Transfection experiments demonstrated that the alternative RNA splicing of the 
            
        murine aA-crystallin gene is neither tissue- nor species-specific. Crystallin 
            
        promoters were analyzed by fusion to the bacterial chloramphenicol acetyl 
            
        transferase (CAT) gene in the pSVO-CAT expression vector. Cell-free 
            
        transcription experiments using a Hela cell extract was used to identify the 
            
        core promoter of the chicken 6- and murine oA-crystallin promoters. Transient 
            
        transfection experiments using cultured lens epithelia and production of 
            
        transgenic mice demonstrated tissue-specific and developmental controls 
            
        operating in the crystallin promoters. Both positive and putative negative 
            
        regulatory sequences were Indicated. The murine oA-crystallln promoter 
            
        (sequences -36'4 to ♦'45) when fused to the SVi40 T-antigen gene neoplastically 
            
        transformed lens cells in transgenic mice. Thus, these experiments Initiate 
            
        genetic engineering In the visual system. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00078-09 LOP 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985. to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 characters or less Title must lit on one line between the borOers ) 
            
         
            
        Histopathology of Human Dystrophies and Degeneration 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust other pfolessionai personnel below the Pnncipai Investigator ) (Name, title, labofatory. ana mtutjte affiliation) 
            
         
            
        PI: Merlyn M. Rodrigues M.D.,Ph.D. Head, Section on LOP, NEI 
            
         
            
        Ophthalmic Pathology 
            
         
            
        Others: Joseph Hackett B.S. Biologist LOP, NEI 
            
         
            
        Reginald Gaskins Histologist LOP, NEI 
            
         
            
        COOPERATING UNITS (It any) 
            
         
            
        Department of Ophthalmology, University of Iowa, Iowa City 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Ophthalmic Pathology 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Pathology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        National Eve Institute. NIH. Bethesda, MP 20205 
            
         
            
        TOTAL MAN- YEARS 
            
        0.2 
            
         
            
        PROFESSIONAL 
            
        0.1 
            
         
            
        OTHER 
            
        0.1 
            
         
            
        CHECK APPROPRIATE BOX(ES| 
            
         
            
        B (a) Human subjects 
            
        D (a1) Minors 
            
        G (a2) Interviews 
            
         
            
        D (b) Hunnan tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanaa'd unreduced type Do not etceed the space provided ) 
            
         
            
        Human corneal dystrophies and degenerations which have been clinically documented 
            
        are studied as keratoplasty specimens with histochemical stains, scanning and 
            
        transmission electron microscopy, and Immunologic techniques in an attempt to 
            
        elucidate pathogenetic mechanisms. This approach has provided insight into cell- 
            
        to-cell relationships in the normal and diseased states. In patients with 
            
        primary and recurrent macular corneal dystrophy, intercellular and extracellular 
            
        accumulation of f ibrillogranular material was observed in the corneal stroma, 
            
        Descemet's membrane, and corneal endothelium. The presence and production of 
            
        collagen, glycoconjugates, and collagenase have been investigated with 
            
        immunofluorescent electrophoretic, and chromatographic methods. The lectin 
            
        binding patterns were compared in corneas from patients with macular dystrophy 
            
        and control. The characterization of amyloid in lattice corneal dystrophy and 
            
        corneal amyloid degeneration was performed using immunohistochemical stains and 
            
        biochemical analysis. Lack of AA reactivity was observed in corneal amyloid 
            
        deposits. Keratoplasty specimens from granular corneal dystrophy and controls 
            
        were examined by combinations of Immunohistological stains, transmission electron 
            
        microscopy, and SOS gel electrophoresis. In granular dystrophy, the deposits 
            
        consisted of phospholipid with microfibrillar protein at the edges. Corneal 
            
        buttons from patients with Fuchs' dystrophy had varying degrees of clinical edema 
            
        measured in most cases by preoperative optical ultrasonic pachymetry. 
            
        Histologically, marked thickening of Descemet's membrane and abnormal corneal 
            
        endothelium corresponded to areas of severe clinical edema and were usually 
            
        located in the central and paracentral regions. Clinical edema was not present 
            
        unless accompanied by marked thickening of Descemet's membrane with multiple 
            
        guttata and attenuation of corneal endothelium. The peripheral cornea was 
            
        relatively clear clinically and showed minimal histologic changes. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00096-08 LOP 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985, to September 30. 1986 
            
         
            
        TITLE OF PROJECT (80 c/taracttn or l»$s Titte must tit or om /me belwaen tr>» bonters ) 
            
         
            
        Cllnicopathologic Studies of Human Ocular Diseases 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi ottf' prol»SiK>tfi ptrsonnti btio* tht Prmaptl Invsiigaior ) (N*me. one. laboratory, ana ncMi/re ^lUabort) 
            
         
            
        PI: Merlyn M. Rodrigues M.D., Ph.D. 
            
         
            
        Others: David Bardenstein M,D. 
            
         
            
        Joseph Hackett B.S. 
            
        Reginald Gaskins 
            
         
            
        Head, Section on LOP, NEI 
            
        Ophthalmic Pathology 
            
         
            
        Guest worker LOP, NEI 
            
         
            
        Biologist LOP, NEI 
            
         
            
        Histologist LOP, NEI 
            
         
            
        COOPERATING UNITS (H any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Ophthalmic Pathology 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Pathology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        National Eye Institute, NEI, Bethesda, MP 20205 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        o,3_ 
            
         
            
        PROFESSIONAL 
            
         
            
        0.2 
            
         
            
        OTHER 
            
         
            
        0.1 
            
         
            
        CHECK APPROPRIATE B0X(ES| 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        D (b) Human tissues Gd (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanOard ooreOucetf type Do not etceoO the space provKle<l ) 
            
         
            
        Patients with localized ocular diseases or with ocular manifestations of 
            
        systemic disease are examined clinically, and photographic documentation is made 
            
        of significant findings. Biopsy specimens or autopsy eyes from these patients 
            
        are examined by electron microscopy and histochemical stains. Studies are 
            
        performed on patients with ocular manifestations of systemic diseases. 
            
         
            
        Forty patients with acquired immunodeficiency syndrome (AIDS) were examined for 
            
        ocular abnormalities. Twenty of these patients died and the eyes were obtained 
            
        for culture and histologic examination. These patients have multiple 
            
        opportunistic infections and neoplasms as the result of a severe depression of 
            
        cellular immunity. Fifty percent of all patients with AIDS and 75% of the 
            
        autopsy group have ocular signs attributable to AIDS. Ocular findings were 
            
        confined to four major categories: cytomegalovirus (CMV) retinitis (10 
            
        patients), retinal cotton wool spots (11 patients), conjunctival Kaposi's 
            
        sarcoma (2 patients), and neuro-ophthalmic motility abnormalities (3 
            
        patients). Cytomegalovirus retinitis was a significant cause of visual loss.^ 
            
        Seven of ^0 autopsy eyes had hand-motion or worse vision prior to the patient's 
            
        death because of CMV and progressed to involve the entire retina in three to six 
            
        months resulting in a gliotic retina membrane. Disseminated systemic 
            
        histoplasmosis was observed in a patient with AIDS. In 3 patients, the effect 
            
        of argon laser treatment was shown to be ineffective in halting the spread of 
            
        cytomegalovirus in patients with AIDS. 
            
         
            
        Immunohistochemical stains are performed on patients with retinitis pigmentosa 
            
        and retinoblastoma to test for the presence of neuronal and glial proteins. 
            
        Electron microscopy is also performed in selected cases. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00114-06 LOP 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985. to September 30. 1986 
            
         
            
        TITLE OF PROJECT (BO chtrtcttrs or less Title must tit on one hne between the txyoers ) 
            
         
            
        Histopathologic Studies of Animal Models of Human Ocular Diseases 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust other professional personne' eeto* the Pnncipe! Investigator ) (Name, title, laboratory, ana institute aflMtion) 
            
         
            
        PI; 
            
         
            
        Others: 
            
         
            
        Merlyn M. Rodrlgues 
            
         
            
        M.D.. 
            
         
            
        Reginald Gaskins 
            
         
            
         
            
        Joseph Hackett 
            
         
            
        B.S 
            
         
            
        Anastasios Halkias 
            
         
            
        M.D. 
            
         
            
        Barbara Wiggert 
            
         
            
        Ph.D. 
            
         
            
        Gerald Chader 
            
         
            
        Ph.D. 
            
         
            
        .Ph.D. 
            
         
            
        Head, Section on LOP, NEI 
            
        Ophthalmic Pathology 
            
         
            
        Histologist LOP, NEI 
            
         
            
        Biologist LOP, NEI 
            
         
            
        Fogarty Fellow LOP, NEI 
            
         
            
        Research Chemist LVR , NEI 
            
         
            
        Chief, Laboratory LVR, NEI 
            
        of Vision Research 
            
         
            
        COOPERATING UNITS (» any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Ophthalmic Pathology 
            
         
            
        SECTION 
            
         
            
        Section on Ophthalmic Pathology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        National Eye Institute. NIH. Bethesda. MD 20205 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.2 
            
         
            
        PROFESSIONAL 
            
        0.1 
            
         
            
        OTHER 
            
         
            
        0.1 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        E (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided ) 
            
         
            
        Immunocytochemical staining of fresh frozen rhesus monkey retinas was performed 
            
        using indirect immunofluorescence and immunoperoxidase (avidin-biotin- 
            
        complex). Affinity-purified antibodies to interphotoreceptor retinoid-binding 
            
        protein (IRBP) obtained from rabbits was used to localize IRBP on frozen 
            
        sections. Fresh frozen pineal glands from the same species were stained by the 
            
        avidin-biotin-peroxidase method. In addition, retinas from rod-dominant and 
            
        cone-dominant species were examined. Immunocytochemical staining revealed 
            
        localization of IRBP in the interphotoreceptor space of peripheral equatorial 
            
        and posterior retina, with marked decrease in staining in the fovea. A 
            
        transition zone was noted at the ora serrata, where staining was present in the 
            
        peripheral retina up to the ora serrata, but was absent in ciliary epithelium. 
            
        Cone-dominant retinas (chick and turtle) showed lack of reactivity to IRBP. 
            
        Rod-dominant rat retina showed localization of IRBP to the interphotoreceptor 
            
        space. Primate and rat pineal showed immunocytochemical localization of IRBP. 
            
        Spontaneously occurring anterior chamber segment anomalies in DBA/2 mice were 
            
        studied by slit-lamp biomicroscopy and light and transmission electron 
            
        microscopy (TEM). The opacities consisted of aggregates of basophilic material 
            
        In the superficial stroma which stained positively for elastin TEM revealed that 
            
        they were electron dense and extracellular. Iris abnormalities consisted of 
            
        stromal atrophy and proliferation of corneal endothelium and basement membrane 
            
        across the iris surface and trabecular meshwork . The corneal opacities seen in 
            
        DBA/2 mice show a striking similarity to those which characterize familial band- 
            
        shaped nodular keratopathy, a form of corneal elastosis. 
            
         
            
        ANNUAL REPORT 
            
         
            
        NATIONAL EYE INSTITUTE 
            
         
            
        October 1, 1985 - September 30, 1986 
            
         
            
        REPORT OF THE CHIEF, LABORATORY OF RETINAL CELL AND MOLECULAR BIOLOGY 
            
         
            
        Gerald J. Chader, Ph.D. 
            
         
            
        The Laboratory of Retinal Cell and Molecular Biology is a newly 
            
        formed unit within the National Eye Institute. It draws together former 
            
        members of the Laboratory of Vision Research who have a common interest in 
            
        basic and applied studies on the neural retina and associated tissues such 
            
        as pigment epithelium. As the name implies, aspects of retinal cell 
            
        biology as well as molecular biology are being studied both in normal and 
            
        in diseased tissues. In particular, there is an emphasis on the study of 
            
        inherited retinal diseases as exemplified by retinitis pigmentosa and 
            
        retinoblastoma. 
            
         
            
        The laboratory consists of three separate but cooperating Sections 
            
        each investigating a particular aspect of retinal function. Following are 
            
        highlights of some of the research conducted by members of the LRCMB over 
            
        the last year: 
            
         
            
        Section on Cell Biology : As Chief of this section, Dr. Paul O'Brien 
            
        leads the NEI effort in studying unique biochemical events in the retina 
            
        related to photoreceptor physiology. In normal retinas, he has continued 
            
        to define specific reactions leading to acylation of rhodopsin, the visual 
            
        pigment. Palmitate is added to newly synthesized as well as mature 
            
        rhodopsin molecules and may be involved in important cellular processes 
            
        such as sorting and transport of protein from the Golgi apparatus and in 
            
        disc membrane assembly and outer segment membrane repair mechanisms. In 
            
        parallel, he has been investigating synthesis and degradation of proteins 
            
        and phospholipids in normal retinas and in animal models of inherited 
            
        retinal degeneration. Of potential importance is the apparently abnormal 
            
        phospholipid metabolism that Dr. O'Brien has now observed in poodles 
            
        affected with Inherited rod-cone degeneration. These animals exhibit an 
            
        abnormally low rate of photoreceptor outer segment renewal prior to the 
            
        onset of degeneration. 
            
         
            
        Section on Biochemistry : Dr. Barbara Wlggert has continued her 
            
        Impressive work on the biochemistry and function of IRBP, the interphoto- 
            
        receptor retinoid-bindlng protein. It is now clear that this protein is a 
            
        unique, new type of retinoid transport protein designed for the extra- 
            
        cellular transport of retinoids between the photoreceptor elements of the 
            
        neural retina and vitamin A stores in the retinal pigment epithelium. 
            
        This work takes on added significance with the discovery of substantial 
            
        amounts of IRBP in the pineal organs of several species. Although the 
            
        function of the protein in the pineal gland in presently not clear, it may 
            
        indicate a hitherto unknown role of retinoids and their transport in this 
            
        secondary organ of phototransduction. 
            
         
            
        Section on Gene Regulation ; In collaboration with Dr. Wlggert, Dr. 
            
        John Nickerson and his group have made excellent progress In studying the 
            
        molecular biology of the IRBP molecule. cDNAs for IRBP, for example, have 
            
        now been established and verified and about one half of the nucleotide 
            
        sequence has been determined. Bovine and human genomic clones have also 
            
        been established and progress has been made concerning the chromosomal 
            
        location of the IRBP gene. Aspects of IRBP synthesis are also under 
            
        investigation. It is of interest that the size of the IRBP mRNA is 
            
        extraordinarily large, indicating a long uncoded region. In situ 
            
        hybridization studies have indicated that the probable site of IRBP 
            
        synthesis in the retina is predominantly in the rod photoreceptor cell. 
            
        These studies further strengthen the argument that IRBP is intimately 
            
        involved in general processes of photoreception. 
            
         
            
        Other members of the Section on Gene Regulation have focused their 
            
        work on attempting to find the biochemical lesionCs) in animals exhibiting 
            
        early-onset retinal degeneration. In particular, Mr. R.T. Fletcher has 
            
        studied genetic crosses of rd and rds mice with reference to the cyclic 
            
        GMP second messenger system in photoreceptor cells and has found a direct 
            
        gene-dose relationship between a photoreceptor cell cyclic GMP phospho- 
            
        diesterase enzyme and the rds gene. This would seem to be of importance 
            
        in linking abnormal retinal concentrations of cyclic GMP with the rds gene 
            
        responsible for degeneration of the retina. 
            
         
            
        Another hereditary disease under investigation Is retinoblastoma. 
            
        Dr. A. Kyritsis has made substantial progress in understanding factors 
            
        related to growth and differentiation of human Y-79 retinoblastoma cells 
            
        in culture. One of the most controversial questions concerning this type 
            
        of cancer over the years, has been the origin of the cells. From Dr. 
            
        Kyritsis' work, it now appears that the cells are multipotential blast 
            
        cells capable of at least partial differentiation into most if not all of 
            
        the general cell types found in the normal retina. These include 
            
        neuronal, glial and pigment epithelial elements. This has been a 
            
        particularly satisfying finding, since it explains most of the seemingly 
            
        contradictory previous evidence in the literature and it Indicates that 
            
        the tumor cells, depending on their particular surroundings (substratum, 
            
        differentiating agents, etc.), can develop along any one or more of these 
            
        pathways as the tumor grows. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        I PROJECT NUMBER 
            
         
            
        Z01 EY 00070-09 LRCMB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30. 1986 
            
         
            
        TITLE OF PROJECT (80 characltrs or t»%i Title must til or one knt between the borders ) 
            
         
            
        Vitamin A and Ocular Tissues 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi otrtei prolessionai persortnel below tt>e Principal Invtsligatoi ) (Name title laboratory, and ntlitute attihation) 
            
         
            
        PI: Barbara Wiggert Ph.D. Head, Section on LRCMB, NEI 
            
         
            
        Biochemistry 
            
         
            
        Others; Ling Lee 
            
         
            
        Michael Redmond 
            
        Gerald J. Chader 
            
         
            
        M.S. 
            
         
            
        Chemist 
            
         
            
        Ph.D. 
            
         
            
        Staff Fellow 
            
         
            
        Ph.D. 
            
         
            
        Chief 
            
         
            
        LRCMB, NEI 
            
        LRCMB, NEI 
            
        LRCMB, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        LSU Eye Center, New Orleans, LA (N. Bazan, T. Reddy) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Retinal Cell and Molecular Biology 
            
         
            
        SECTION 
            
         
            
        Section on Biochemistry 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH. Bethesda. Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        _2JL 
            
         
            
        PROFESSIONAL 
            
         
            
        J^J_ 
            
         
            
        OTHER 
            
         
            
        1-0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        E (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use Standard unreduced type Do not exceed ffte space provided ) 
            
         
            
        An enzyme-linked immunosorbent assay (ELISA) for monkey and human Interphoto- 
            
        receptor Retinoid-Binding Protein (IRBP) was used to quantitate IRBP in normal and 
            
        diseased human retinas and retinoblastoma tumors. IRBP levels were uniformly low 
            
        in retinas from human cases of hereditary retinal degenerations even in areas in 
            
        which photoreceptors remained. IRBP was present in several retinoblastoma tumors 
            
        examined. 
            
         
            
        The amino terminal sequences of monkey and bovine IRBPs were extended to over 30 
            
        residues each. The major monkey sequence had an additional 5 amino acid residues 
            
        at its amino terminus not observed with bovine IRBP, although the sequences showed 
            
        extensive homology. The amino terminal sequence of human IRBP was identical to 
            
        that of the monkey, and the two sequences were present in equal amount. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00015-21 LRCMB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 chartclen or less Tirie musi til on ont Imt Oarwatr the borders ) 
            
         
            
        The Cell Biology of the Vertebrate Retina 
            
         
            
        PRINCIPAL INVESTIGATOR lUsl ottte- ptoiessionai personnel beior* ttfe Prmcipai Irwestigator ) (Nvrye. title, laboratory, ana nsmute aHUialion) 
            
         
            
        PI: Paul J. O'Brien Ph.D. 
            
         
            
        Others: Robert St. Jules Ph.D. 
            
         
            
        Head, Section on 
            
         
            
        Cell Biology 
            
         
            
        Staff Fellow 
            
         
            
        LRCMB, NEI 
            
        LRCMB, NEI 
            
         
            
        COOPERATING UNITS (if any) 
            
         
            
        Department of Anatomy, University of Toronto (M. J. Irons) 
            
         
            
        LAB'BRANCH 
            
         
            
        Laboratory of Retinal Cell and Molecular Biology 
            
         
            
        SECTION 
            
         
            
        Section on Cell Biology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        1.6 
            
         
            
        PROFESSIONAL 
            
         
            
        1.6 
            
         
            
        OTHER 
            
         
            
        Q.Q 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        n (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        D (b) Human tissues S (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standaro unreduced type Do not exceed tfie space provided I 
            
         
            
        The acylation of rhodopsin with palmitic acid has been studied to determine the 
            
        function of this modification in the intracellular transport of rhodopsin and its 
            
        incorporation into functional disc membranes. Palmitate is added to rhodopsin 
            
        shortly after the polypeptide is synthesized. Most of the new rhodopsin 
            
        molecules are retained in the endoplasmic reticulum for at least six hours, 
            
        suggesting that transport to the outer segment may not be a continuous process. 
            
        Palmitate is also added to mature rhodopsin molecules in the outer segment 
            
        indicating a possible repair mechanism or a physiologically important cycle of 
            
        removal and replacement. The phospholipids of the outer segment turn over 
            
        continuously but retain and, in- the case of phosphatidylethanolamine , even 
            
        Increase the level of labeling with palmitic acid. Thus, this fatty acid 
            
        undergoes a continuous process of reutilization. 
            
         
            
        Cytidine monophosphate, a by-product of phospholipid turnover, is cleaved by a 
            
        manganese-dependent nucleotidase in rod outer segments. Histochemical studies 
            
        Indicate that this enzyme is transported from the pigment epithelium to the 
            
        outer segments in anticipation of disc shedding and may represent a class of 
            
        degradative enzymes involved in this process. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00016-19 LRCMB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 charicteri (y l9Si Title must tit on on« line beiwoen the boniers ) 
            
         
            
        The Biochemistry of Normal and Dystrophic Retinas 
            
         
            
        PRINCIPAL INVESTIGATOR fUS! other proteisiontl personnel below ttte Pnnapai Investigaio' ) (Name. ODe. laOofiory, ana ntuute a/raUtxyt; 
            
         
            
        PI; 
            
         
            
        Paul J. O'Brien 
            
         
            
        Others: Peter A. Dudley 
            
         
            
        Ph.D. 
            
         
            
        Ph.D. 
            
         
            
        Head, Section on 
            
         
            
        Cell Biology 
            
         
            
        LRCMB, NEI 
            
         
            
        ECP, 
            
         
            
        NEI 
            
         
            
        COOPERATING UNITS (H any) 
            
         
            
        School of Veterinary Medicine, University of Pennsylvania (G. Aguirre) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Retinal Cell and Molecular BioloRV 
            
         
            
        SECTION 
            
         
            
        Section on Cell Biology 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI. NIH. Bethesda. Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        0.2 
            
         
            
        PROFESSIONAL 
            
         
            
        0.2 
            
         
            
        OTHER 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOXlESi 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues S (c) Neither 
            
         
            
        SUMMARY OF WORK (Use slandara unreduceO type Do not exceed the space proviOed ) 
            
         
            
        This project examines biochemical events unique to the retina, particularly the 
            
        synthesis and modification of photoreceptor membrane components, in the retinas of 
            
        vertebrates which can be affected by inherited retinal degenerations. The 
            
        synthesis of the visual pigment, rhodopsin, occurs at a normal rate as measured by 
            
        radioactive leucine incorporation following intravitreal injection in the eyes of 
            
        miniature poodles affected with progressive rod-cone degeneration. Similarly, the 
            
        glycosylation and acylation of rhodopsin were found to be normal following 
            
        intravitreal injection of labeled fucose or palmitic acid, respectively. However, 
            
        phospholipid synthesis or degradation, measured by radioactive palmitic acid 
            
        incorporation, appears to be different in the affected dogs, suggesting a possible 
            
        metabolic defect in this inherited disorder. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY OOU8-13 LRCMB 
            
         
            
        TITLE OF PROJECT (80 cnaraclen or lea Title must til on on* hnt belwaen ffte borOers ) 
            
         
            
        Cyclic Nucleotides and Visual Control Mechanisms 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi otttt' ptolaisional personnel tWOiv We Pnncipei Investigator ) (Name, title laboratory, ana ntlitule altmation) 
            
         
            
        PI: Gerald J. Chader Ph.D. Chief LRCMB, NEI 
            
         
            
        Others: Susan Gentleman 
            
         
            
        R. Theodore Fletcher 
            
        Robert L. Somers 
            
        C. Lai Kapoor 
            
         
            
        Ph.D. 
            
         
            
        Expert 
            
         
            
        LRCMB, 
            
         
            
        NEI 
            
         
            
        M.S. 
            
         
            
        Chemist 
            
         
            
        LRCMB, 
            
         
            
        NEI 
            
         
            
        B.S. 
            
         
            
        Chemist 
            
         
            
        LRCMB, 
            
         
            
        NEI 
            
         
            
        Ph.D. 
            
         
            
        Guest Worker 
            
         
            
        LRCMB, 
            
         
            
        NEI 
            
         
            
        COOPERATING UNITS (H any) 
            
         
            
        Section on Medical Genetics, School of Veterinary Medicine, University of 
            
        Pennsylvania (G. Aguirre) ; Department of Anatomy, Erasmus University, Rotterdam, 
            
        The Netherlands (S. Sanyal) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Retinal Cell and Molecular Biology 
            
         
            
        SECTION 
            
         
            
        Section on Gene Regulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 
            
         
            
        20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        2.8 
            
         
            
        PROFESSIONAL 
            
         
            
        1.8 
            
         
            
        OTHER: 
            
         
            
        1.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        C (al) Minors 
            
        D (a2) Interviews 
            
         
            
        E (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use stanUard unreduced type Do not exceed ttie space provided ) 
            
         
            
        Cyclic nucleotides and protein phosphorylation play a special role in photo- 
            
        receptor control mechanisms. 
            
         
            
        1. A calcium phospholipid-dependent protein kinase (C-kinase) phosphorylates 
            
        specific proteins of the rod outer segment organelle. 
            
         
            
        2. A specific extracellular cyclic CMP phosphodiesterase was identified in the 
            
        retinal extracellular matrix. 
            
         
            
        3. Cyclic AMP-dependent protein kinases were found to be abnormal in human 
            
        retinoblastoma cells in culture. 
            
         
            
        ^. Cyclic CMP was found to be abnormally high in photoreceptor cell synapses of 
            
        an animal model of inherited retinal degeneration. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00:2i«-06 LRCME 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TITLE OF PROJECT (BO charactert or lass Title must tit on one line between ttie bortiers I 
            
         
            
        Metabolism of the Retina and Pigment Epithelium 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi other prolessional personnel below tfie Principal Investigator ) (Name, title, laboratory, ana institute altiiiationi 
            
         
            
        PI: Gerald J. Chader Ph.D. Chief LRCMB, NEI 
            
         
            
        Others: Shay-Whey M. Koh Ph.D. 
            
        Athanasslos P. Kyritsis M.D. 
            
        R. Theodore Fletcher M.S. 
            
         
            
        Staff Fellow 
            
        Visiting Fellow 
            
        Chemist 
            
         
            
        LRCMB, NEI 
            
        LRCMB, NEI 
            
        LRCMB, NEI 
            
         
            
        COOPERATING UNITS (it any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Retinal Cell and Molecular Biology 
            
         
            
        SECTION 
            
         
            
        Section on Gene Regulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda. Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        PROFESSIONAL 
            
         
            
        2.1 
            
         
            
        2.1 
            
         
            
        OTHER 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOX(ESl 
            
         
            
        D (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) intervievi^s 
            
         
            
        H (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standara unre<luce<3 type Do not exceed the space provided ) 
            
         
            
        Metabolic characteristics of r 
            
        nation. 
            
         
            
        1 . The response of cultured c 
            
        neurotransmitters and neuromod 
            
        intestinal peptide (VIP). A s 
            
        epithelial cell membranes; als 
            
        response to VIP have been iden 
            
         
            
        2. Human retinoblastoma cells 
            
        culture into the three major c 
            
        glia and pigment epithelial ce 
            
        factors appear to play a role 
            
        attachment. 
            
         
            
        etinal cells in tissue culture are under exami- 
            
         
            
        ells of the retinal pigment epithelium to various 
            
        ulators have been examined, especially to vasoactive 
            
        pecific VIP receptor has been identified on pigment 
            
        0, soluble and membrane proteins phosphorylated in 
            
        tified. 
            
         
            
        in culture can be Induced to differentiate in 
            
        ell types seen in the normal retina, le, neurons, 
            
        lis. Laminin and appropriate other attachment 
            
        in retinoblastoma cell differentiation as well as 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        Z01 EY 00196-03 LRCMB 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985 to September 30, 1986 
            
         
            
        TrruE OF PROJECT (BO chanclars ly less Tm must In on one hne between the borOers ) 
            
         
            
        Molecular Genetics of the Eye and Ocular Diseases 
            
         
            
        PRINCIPAL INVESTIGATOR (Usl ott>er prolessionai personnel below tne Principal Investigator ) (Name title laboratory an<t msMute filiation) 
            
         
            
        PI: John M. Nickerson Ph.D. Senior Staff Fellow LRCMB, NEI 
            
         
            
        Others: Diane Borst 
            
         
            
        Shirley Rainier 
            
        T. Michael Redmond 
            
         
            
        Ph.D. Guest Worker 
            
        Ph.D. Staff Fellow 
            
        Ph.D. Staff Fellow 
            
         
            
        LRCMB, NEI 
            
        LRCMB, NEI 
            
        LRCMB, NEI 
            
         
            
        COOPERATING UNITS (il any) 
            
         
            
        Zoology Department, University of Lund, Lund, Sweden (Theo Van Veen) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Retinal Cell and Molecular Biology 
            
         
            
        SECTION 
            
         
            
        Section on Gene Regulation 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, 
            
         
            
        Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        2.5 
            
         
            
        PROFESSIONAL 
            
         
            
        2.5 
            
         
            
        OTHER 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        S (a) Human subjects 
            
        D (a1) Minors 
            
        n (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        Summary of work (Use stanaara unreauced type Do not eiceeO lf>e space proviOeO ) 
            
         
            
        My laboratory is presently isolating and characterizing recombinant DNA molecules 
            
        necessary for the study of the structure and expression of IRBP (Interphoto- 
            
        receptor Retinoid-Binding Protein). Clones and partial sequences froo bovine IRBP 
            
        have been obtained. We have cloned and completely sequenced six overlapping cDNA 
            
        clones that constitute about 3500 bases of the 7000 base long bovine IRBP mRNA. 
            
        The IRBP mRNA is unusually long especially given that the polypeptide encoding 
            
        region of the mRNA should only require about 3600 bases. There is only one band 
            
        on a Northern blot suggesting that there is only one IRBP mRNA species. The 
            
        clones were used as probes for in situ hybridizations to frozen sections of bovine 
            
        and monkey retinas. In large, only the rod cell perlkarya were labelled with the 
            
        probe. This showed us that the gene is regulated and expressed only in the rod 
            
        cell, and it defined the site of synthesis of the IRBP polypeptide as the rod 
            
        cell. Part of the gene for bovine IRBP has been cloned. Partial DNA sequence 
            
        analysis revealed a perfect match of 75 bases of the cDNA and genomic clones. The 
            
        sequences diverged at a consensus splice acceptor site in the gene clone, 
            
        indicating an intron-exon boundary. We have obtained a putative genomic clone for 
            
        the human gene, but it remains to be proven (by DNA sequencing) that this clone Is 
            
        authentic. We have begun to characterize the IRBP gene by analysis of Southern 
            
        genomic blots. We have shown that the gene is present in only one copy per 
            
        haploid genome in a variety of species. In human, the gene Is not on the 
            
        X-chromosome, since hybridizing bands from male and female DNA samples are the 
            
        same intensity. We are now In the process of mapping the precise chromosome. 
            
         
            
        ANNUAL REPORT 
            
         
            
        NATIONAL EYE INSTITUTE 
            
         
            
        October 1, 1985 - September 30. 1986 
            
         
            
        REPORT OF THE CHIEF, LABORATORY OF SENSORIMOTOR RESEARCH 
            
        Robert H. Wurtz, Ph.D. 
            
         
            
        This ie the eighth Annual Report of the Laboratory of Sensorimotor Research 
            
        and is intended to describe work in the Laboratory over the last two years. I 
            
        would like in this somewhat more flexible report to concentrate on the relevance 
            
        of work in the Laboratory to several fundamental problems of visual neuroscience. 
            
        In particular, I would like to emphasize the contribution of our analysis of the 
            
        visual and the oculomotor system in the monkey to an understanding of these sys- 
            
        tems in man. 
            
         
            
        The aspect of brain function that we study, the visual and oculomotor sys- 
            
        tem, has been shown repeatedly to be very similar in man and monkey so that the 
            
        experiments we perform on the monkey serve as a model for man. Behavioral, phy- 
            
        siological, and anatomical experiments possible on the monkey have given us our 
            
        most fundamental understanding of how the visual and oculomotor functions of the 
            
        brain of man are likely to be organized. In addition I think several investiga- 
            
        tions in the Laboratory in the last several years illustrate how the precise 
            
        analysis possible in the visual-oculomotor system has allowed exploration of fun- 
            
        damental questions in brain research. 
            
         
            
        One of these questions is how we are able to obtain sensory information in 
            
        spite of the continual movements we make in our environment. The pinnacle of 
            
        this stability is the ease with which we maintain stable vision in spite of our 
            
        own movement of body, head, and eyes. Much of this stability of the eye is due 
            
        to the vestibular-ocular reflex, a system that Dr. F. A. Miles in the Laboratory 
            
        has studied over a period of years. In this system, the balance mechanisms in 
            
        the ear lead to eye movement that compensates for head and body movement. In 
            
        addition to this vestibular mechanism, another system has been studied by Dr. 
            
        Miles that provides fine tuning of this stabilization. This ocular following 
            
        response occurs with the incredibly short latency of only about 50 msec following 
            
        a rapid or saccadic eye movement across a visually patterned environment. Furth- 
            
        ermore, the ocular following is enhanced following such eye movements just at the 
            
        time when increased stabilization of vision is essential. The mechanisms under- 
            
        lying this visual motor event can be dissected apart by replacing the rapid eye 
            
        movement with an equally rapid shift in the visual environment: the ocular fol- 
            
        lowing response can still be invoked easily. However, when a large visual scene 
            
        is quickly moved in a saccade-like way the ocular following response is actually 
            
        suppressed. This powerful inhibitory mechanism that emanates from the peripheral 
            
        visual field probably prevents the eye from tracking the visual disturbances 
            
        created by the rapid eye movements as they sweep the visual scene across the 
            
        retina. Thus, not one visual mechanism is involved in stabilization, but rather 
            
        two interacting ones: one to produce the stabilization of the eye, the other to 
            
        produce a suppression of that stabilization when it is inappropriate. These 
            
        experiments demonstrate graphically the series of exact and elaborate mechanisms 
            
        that primates use to maintain the essential conditions for normal vision. The 
            
         
            
        deficits in this type of stabilization, which may occur with the diseases of man, 
            
        can only begin to be diagnosed if the series of interlocking mechanisms is 
            
        clearly understood and this understanding can only be derived from the type of 
            
        carefully controlled experiments such as those of Dr. Miles. 
            
         
            
        Effective vision not only demands stability during periods of fixation on a 
            
        given object, but it also demands the ability to shift the highly developed cen- 
            
        tral or foveal region of the retina from one part of the visual field to another. 
            
        This selective function, frequently referred to as selective visual attention, 
            
        has been studied over a number of years in the Laboratory. Dr. D. L. Robinson 
            
        and his collaborators have continued this work in both monkey and man. His pre- 
            
        vious physiological experiments had shown that a region of cerebral cortex, the 
            
        posterior parietal cortex, was critically involved in tasks related to attention, 
            
        and that the pulvinar nuclei of the thalamus, a step on the visual pathway reach- 
            
        ing from the brainstem to parietal cortex, were also critically involved in this 
            
        selective attention mechanism. This behavioral attention in monkeys can be stu- 
            
        died by giving the monkey a cue indicating the area of the visual field that is 
            
        important and then testing the speed of a monkey's subsequent response to a 
            
        stimulus in that field. By suppressing the activity of one area area of the 
            
        brain with minute injections of chemicals while the monkey performs this task. 
            
        Dr. Robinson has been able to show the involvement of that area of the brain in 
            
        this type of selective attention. These methods of behavior testing have now 
            
        been extended to human patients whose disease might involve the areas of the 
            
        brain identified in the monkey as being related to visual attention. The tests 
            
        have provided a constellation of deficits that characterize patients with lesions 
            
        of the parietal area of cerebral cortex. In contrast, patients suffering from 
            
        schizophrenia or from Alzheimer's disease might show some deficits in attentional 
            
        tasks, but not the same set of deficits seen in those patients with parietal 
            
        lesions. Thus, a set of experiments growing out of an analysis of the neural 
            
        systems within the brain of monkeys has been developed that allows the diagnosis 
            
        of damage to one part of the brain of man. Furthermore, this analysis of visual 
            
        attention shows that the highest level of behavior in man can be subjected to 
            
        precise behavioral analysis and related to precise neural structures within the 
            
        brain. 
            
         
            
        Possibly the region of the cerebral cortex involved in the highest neural 
            
        processing is the frontal lobe, and it is in this region that Dr. H. E. Goldberg 
            
        and his collaborators have concentrated their analysis of one type of eye move- 
            
        ment, the rapid, or saccadic eye movements which I have referred to above. The 
            
        pathways for this particular type of movement, that connects the visual signals 
            
        arriving from the eye to the activation of the eye muscle to move the eye towards 
            
        the target, is probably the best understood sensorimotor pathway within the 
            
        brain. What is striking about this system is that there seems to be a separate 
            
        segment related to the same movement made under different conditions: some areas 
            
        of the brain participate in the generation of all saccades; others participate 
            
        only in saccades that are important to an animal's behavior, whether or not the 
            
        saccades are made in response to visual targets. The frontal cortex seems to be 
            
        particularly important for this latter type of movement. The frontal eye fields 
            
        do not, however, send a motor message for the generation of saccades irrelevant 
            
        to a subject's behavior. Ordinarily, the act of attentive fixation filters out 
            
        the signals for irrelevant saccades. Thus Dr. Goldberg and his group found that 
            
        it was more difficult to evoke saccades electrically from the frontal eye fields 
            
        when a monkey was actively looking at a spot of light, and the saccade evoked had 
            
        a characteristic waveform called a square-wave jerk. In collaboration with the 
            
         
            
        Neuro-Ophthalmology Section, Dr. Goldberg noticed that certain patients complain- 
            
        ing of slow reading made square-wave jerks while they attempted to fixate a tar- 
            
        get. Since these eye movements resemble those evoked in the monkey during atten- 
            
        tive fixation, they might in man be a sign of attentional fluctuations, which 
            
        would make the oculomotor system more susceptible to signals for irrelevant sac- 
            
        cades. Since other patients with cerebellar disease have square-wave jerks but 
            
        no reading difficulty, Dr. Goldberg hypothesized that the deficit was not oculo- 
            
        motor instability but rather an attentional deficit which interfered both with 
            
        adequate oculomotor performance and reading. A small number of these patients 
            
        were treated with methy Iphenidate, a drug approved for attentional deficit 
            
        disorders. Not only did the square-wave jerks disappear, but several measures of 
            
        reading performance also improved under treatment. This promising new line of 
            
        clinical research in man would not have been possible without the fundamental 
            
        observations on the frontal eye fields of monkeys. 
            
         
            
        Visual processing in both man and monkey is represented in other regions of 
            
        the cerebral cortex, primarily in the occipital and temporal lobes. One of the 
            
        most promising developments in our understanding of this visual processing has 
            
        been the realization that the analysis might be divided between different subre- 
            
        gions of this region of cerebral cortex. My collaborators and I have studied one 
            
        aspect of this visual processing, that related to visual motion processing and 
            
        its relationship to a type of eye movement that is dependent on such motion, the 
            
        generation of smooth pursuit eye movements. These movements are used to follow a 
            
        slowly moving target in order to keep the target positioned upon the fovea. It 
            
        is interesting to note that this type of eye movement evolves most clearly in 
            
        primates so that in order to study the system in man, one must analyze the 
            
        mechanisms in another primate such as the monkey. Our experiments have demon- 
            
        strated that minute chemical removal of cells in the motion area of cerebral cor- 
            
        tex reduces a monkey's ability to generate pursuit eye movements. Furthermore, 
            
        similar damage to the next step of visual processing produces an additional defi- 
            
        cit, a difficulty in keeping the eye on the target once it is on the fovea but 
            
        only when the target moves toward the damaged side of the brain. It is striking 
            
        that one of the first deficits related to eye movements in man that was specifi- 
            
        cally related to the cerebral cortex was this directed pursuit deficit. Thus, 
            
        with minute lesions in monkeys, we have been able to replicate the deficits seen 
            
        following the uncontrolled and extensive accidents of nature in man. Further- 
            
        more, because we are able to analyze the response of single cells in the monkey, 
            
        we have been able to see the types of cells in a sequence of visual areas, 
            
        including those areas producing the directional deficit. The hypothesis that we 
            
        have developed suggests that the first visual area is related to visual motion 
            
        processing while the next one (related to the directional deficit) has signals 
            
        related to maintaining eye movements that do not depend on the visual input. 
            
        These experiments demonstrate the use of a particular type of eye movement in the 
            
        analysis of visual processing; the removal of a tiny visual area leads to an 
            
        exactly measurable deficit in the eye movement. Tight coupling between the 
            
        visual and oculomotor system makes such an analysis possible in the visual sys- 
            
        tem, and holds promise of precise localization of visual function even within the 
            
        cerebral cortex. 
            
         
            
        Finally, in the studies considered so far, the response of neurons has gen- 
            
        erally been taken as the total number of electrical discharges produced in 
            
        response to a given visual stimulus, or in relation to a particular eye movement. 
            
        However, the work of Dr. L. M. Optican in this Laboratory and Dr. B. J. Richmond 
            
        in the Institute of Mental Health have called this assumption into question at 
            
         
            
        least as far as the visual analysis related to form perception is concerned. 
            
        They have analyzed the distribution of electrical discharges of cerebral cortex 
            
        cells following the presentation of a systematically varied visual stimulus. 
            
        They find that while the rate of discharge conveys information about the visual 
            
        stimulation, the amount of information conveyed by the pattern of discharges is 
            
        twice that carried if one looks at the number of discharges alone. They show 
            
        that in a given cell several independent patterns of spike activity are produced 
            
        by the set of stimuli they used and that these patterns exist simultaneously. 
            
        These experiments in turn led Optican and Richmond to formulate a new hypothesis 
            
        about how information is transmitted in the visual system. They propose that 
            
        these neurons each act as simultaneously active but independent spatial to tem- 
            
        poral filters. Each filter generates a component of the visual response, and 
            
        these components are then combined to form the spike train. While the underlying 
            
        principle of multiple, simultaneous filtering operations has been demonstrated 
            
        for neurons in the primary striate cortex and the inferior temporal cortex, the 
            
        same mechanism may be functioning in other systems as well. Thus, in the case of 
            
        the visual system, where the stimulation can be very exactly controlled using a 
            
        mathematically definable set of stimuli, it has been possible to relate the tem- 
            
        poral pattern of cell discharge to the sensory stimulation. The extent and 
            
        importance of this type of information transmission in the visual system remains 
            
        almost totally unexplored, but represents an exciting possible neuromechanism 
            
        that may help us to understand the way in which the complexities of vision are 
            
        represented within the brain. 
            
         
            
        rii 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985, to September 30, 1986 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00049-08 LSR 
            
         
            
        TITLE OF PROJECT (BO characlarj <y toss TVWe must In or ont hnt betwttn th» borOen ) 
            
         
            
        Cerebral Cortical Mechanisms for Eye Hovements and Visual Attention 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi olher prolessionai personnel below the Pnncipal Investigetor I (Name title laOoratofY ano ntmurr atlmatton) 
            
         
            
        PI: 
            
         
            
        Michael E. Goldberg 
            
         
            
        M.D. 
            
         
            
        Others; 
            
         
            
        Hark Segravee 
            
         
            
        Ph.D. 
            
         
            
        * 
            
         
            
        Deng Shu-yi 
            
         
            
        M.D. , Ph.D 
            
         
            
         
            
        Rolf Boch 
            
         
            
        Ph.D. 
            
         
            
        Chief, NMS 
            
         
            
        Staff Fellow 
            
        Visiting Fellow 
            
        Visiting Fellow 
            
         
            
        LSR, NET 
            
         
            
        LSR, NEI 
            
         
            
        LSR, NEI 
            
         
            
        LSR, NEI 
            
         
            
        COOPERATING UNITS (if any) 
            
         
            
        Department of Anatomy, Howard University (G. B. Stanton) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Sensorimotor Research 
            
         
            
        SECTION 
            
         
            
        Neuro-Ophthalmologic Mechanisms Section 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        4.9 
            
         
            
        PROFESSIONAL 
            
         
            
        3.8 
            
         
            
        OTHER 
            
         
            
        1.1 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        E (a) Human subjects 
            
        G (a1) Minors 
            
        C (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standa'a unreOuced type Do not etceeO ttte space provKtea ) 
            
         
            
        By antidromic stimulation in the superior colliculus of neurons in the arcuate 
            
        frontal eye fields, it was determined that cells bearing eye movement or fixation 
            
        signals but not those with peripheral visual information project to the superior 
            
        colliculus from the frontal cortex. This implies that the cerebral cortex sends 
            
        only a motor message to the brainstem saccadic eye movement system. 
            
         
            
        Monkeys trained on a saccadic adaptation paradigm learn quickly to change the 
            
        amplitude of their saccades in response to intrasaccadic stimulus steps. Stimu- 
            
        lation of the superior colliculus in the adapted case yields the same saccades as 
            
        the unadapted case. The activity of single neurons also shows no evidence of 
            
        adaptation: the visual and movement signals emanating from the colliculus are 
            
        the veridical signals for stimulus and movement, rather than movement signals in 
            
        a visual frame which are modified by the brainstetr.. Thus the change in saccade 
            
        amplitude which occurs as a result of adaptation is compensated for at early 
            
        sites in the neural chain from stimulus to response. 
            
         
            
        A small percentage of humans with reading disorders have fixational instability 
            
        manifest by saccadic intrusions or square-wave jerks while they attempt to fixate 
            
        a spot of light. A single dose of methy Iphenidate decreases or eliminates the 
            
        saccadic intrusions and results in temporary improves in both the ocular mechan- 
            
        ics of oral reading and the reading performance itself. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00153-04 LSR 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985, to September 30, 1986 
            
         
            
        TITLE OF PROJECT ISO chertcttts or toss Titit musi In on one lint belwten me txyotn ) 
            
         
            
        Adaptive Regulation in Primate Oculomotor System 
            
         
            
        PRINCIPAL INVESTIGATOR (ust omer protesiiofiai personnti below me Principal Invasiigatot ) (Ntmt, oot. taAoraKyy ana ncorut* alUkatxgii 
            
         
            
        PI: Frederick A. Miles D.Phil 
            
         
            
        Othera: Lance Optican Ph.D. 
            
         
            
        Reuben Gellman Ph.D. 
            
         
            
        Chief, OCS LSR, NEI 
            
         
            
        Senior Staff Fellow LSR, NEI 
            
        Visiting Fellow LSR, NEI 
            
         
            
        COOPERATING UNITS frf any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Sensorimotor Research 
            
         
            
        SECTION 
            
         
            
        Oculomotor Control Section 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        3.5 
            
         
            
        PROFESSIONAL 
            
         
            
        1.5 
            
         
            
        OTHER 
            
         
            
        2.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        S (a) Human subjects 
            
        D (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standard unreOuceO Type Do not exceed ttie space provKMH ) 
            
         
            
        Experiments were concerned with the initial ocular following responses to tran- 
            
        sient ramp movements of the visual scene in monkeys. These tracking movements 
            
        are important in the stabilization of gaze which is so necessary for good visual 
            
        acuity. We had previously shown in monkeys that responses have short latency (50 
            
        msec) and are transiently enhanced after saccadic eye movements due to the asso- 
            
        ciated visual disturbance. We now report that saccadic eye movements are also 
            
        associated with powerful inhibitory effects on ocular following. This inhibition 
            
        was shown to be visual in origin and to result from stimulation of the peripheral 
            
        region of the visual field. For these experiments the visual field was parti- 
            
        tioned into central and peripheral regions (center, 20° diameter). Sudden shifts 
            
        of the peripheral images elicited brief, powerful inhibition of ocular following 
            
        responses generated by test stimuli at the center. This peripheral suppression 
            
        showed good intraocular transfer: saccade-like movements of the peripheral field 
            
        of one eye suppressed the responses elicited by test ramps applied at the center 
            
        of the other eye. These data indicate that the suppression involves lateral spa- 
            
        tial interactions at/or beyond a site that receives input from the two eyes, and 
            
        hence, must be mediated by the central nervous system. We suggest that this 
            
        suppression functions to prevent the ocular following system froc tracking the 
            
        visual disturbances caused by saccades: saccade-like movements of the central 
            
        field alone produced small transient ocular following responses whereas such 
            
        movements of the periphery or of the whole field did not. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00152-04 LSR 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985, to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 charnclBrs or lass Title must In on one line belwaan me borOers ) 
            
         
            
        Visually Induced Adaptive Changes in Saccadic Innervation 
            
         
            
        PRINCIPAL INVESTIGATOR (Ust oth«r prolassional personnel below me Prmcipa! Investigator j (Name title, laboratory, and ngUute att*ation) 
            
         
            
        PI: Lance Optican Ph.D. Res. Biomedical Engineer LSR, NEI 
            
         
            
        Others: Frederick A. Miles 
            
         
            
        D.Phil. Chief, DCS 
            
         
            
        LSR, NEI 
            
         
            
        COOPERATING UNITS (il anyl 
            
         
            
        David S. Zee, M.D. , Professor Neurology, 
            
         
            
        Johns Hopkins School of Medicine, Baltimore, MD 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Sensorimotor Research 
            
         
            
        SECTION 
            
         
            
        Oculomotor Control Section 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN-YEARS 
            
         
            
        0.8 
            
         
            
        PROFESSIONAL 
            
         
            
        0.8 
            
         
            
        OTHER 
            
         
            
        0.0 
            
         
            
        CHECK APPROPRIATE BOXlESi 
            
         
            
        S (a) Human subjects 
            
        D (a1) Minors 
            
        D (32) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        SUMMARY OF WORK (Use standa'd unreduced type Do no! exceed the space provided I 
            
         
            
        Saccades are the rapid eye movements used to change visual fixation. These eye 
            
        movements are very fast yet they end abruptly, i.e., the eyes do not drift at the 
            
        end of a saccade. This lack of post-saccadic drift is essential for good visual 
            
        acuity after a saccade. Previous experiments in this laboratory have shown that 
            
        the brain actively suppresses post-saccadic drift by altering the levels of 
            
        innervation sent to the muscles during and after a saccade. The adaptive mechan- 
            
        ism for suppression of post-saccadic drift is sensitive to optically-imposed 
            
        post-saccadic retinal slip. Our previous work shoved that a central neural 
            
        mechanism attempted to compensate for this post-saccadic retinal slip by altering 
            
        the gain and time constants of the neural components of saccadic innervation. 
            
        This altered innervation led to a post-saccadic ocular drift that lessened the 
            
        amount of post-saccadic retinal slip. 
            
         
            
        We have previously shown that this central adaptive mechanism was dependent upon 
            
        the cerebellum for its proper function. After a complete cerebel lectocy , monkeys 
            
        developed post-saccadic ocular drift, and were unable to compensate for post- 
            
        saccadic retinal slip. The present work has now shown that the site of this 
            
        functional dependency can be further localized to the cerebellar flocculi and 
            
        paraf locculi. 
            
         
            
        After bilateral f locculectomy , monkeys developed post-saccadic ocular drift. 
            
        When presented with optically-imposed post-saccadic retinal slip, the animals 
            
        were only able to alter their saccadic innervations a little. These post- 
            
        f locculectomy alterations were not large enough to compensate for the retinal 
            
        •lip. Furthermore, this ability was asymmetric, with reductions in gain being 
            
        larger than increases. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PRCXJECT NUMBER 
            
         
            
        ZOl EY 00045-08 LSR 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985, to September 30, 1986 
            
         
            
        TITLE OF PROJECT (80 ctiaracttrz or leu Title must fit on one Ime between tt>e bomet ) 
            
         
            
        Visuomctor Properties of Neurons in the Thalamus 
            
         
            
        PRINCIPAL INVESTIGATOR (Lat other proleiiionai personnel twtow the Prmcipe' Investigator I (Heme mie latxxeiory ena mtoruf* tHikation) 
            
         
            
        PI: David Lee RobinBon Ph.D. Research PhyBioIogist LSR, HEX 
            
         
            
        Others: John W. McClurkin Ph.D. 
            
         
            
        Jon Currie M. D. 
            
         
            
        Mortimer Mishkin Ph.D. 
            
         
            
        Marcie Golomb O.D. 
            
         
            
        Richard Sherins M. D. 
            
         
            
        Edmond FitzGibbon M.D. 
            
         
            
        Guest Worker LSR, NEl 
            
         
            
        Neuro-Ophthalmologist LSR, NEI 
            
         
            
        Laboratory Chief LNP, NIMH 
            
         
            
        Guest Worker LSR, NEl 
            
         
            
        Res. Endocrinologist RR, NICHD 
            
         
            
        Clinical Fellow LSR, NEl 
            
         
            
        COOPERATING UNITS (H »ny) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Sensorimotor Research 
            
         
            
        SECTION 
            
         
            
        Visuomotor Integration Section 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        2.6 
            
         
            
        PROFESSIONAL 
            
         
            
        1.0 
            
         
            
        OTHER 
            
         
            
        1.6 
            
         
            
        CHECK APPROPRIATE BOX(ESl 
            
         
            
        K (a) Human subjects 
            
        C (a1) Minors 
            
        [I (a2) Interviews 
            
         
            
        D (b) Human tissues D (c) Neither 
            
         
            
        Summary of work (Use standard unreduced type Do nor exceed tite space provKled ) 
            
         
            
        We have studied visual spatial attention in humans and monkeys to determine what 
            
        brain areas are important and what each contributes to this cognitive function. 
            
        Visual cues which precede visual targets can modulate reaction times to the tar- 
            
        gets. Cues on the same side as the target (valid cues) are associated with fast 
            
        reaction times; cues on the opposite side (invalid cues) or weak illumination of 
            
        the entire visual field (diffuse cues) are correlated with slow reaction times. 
            
        The cues are hypothesized to control the direction of the subject's attention. 
            
         
            
        Patients with damage to parietal cortex have slowed reaction times to targets 
            
        which follow diffuse cues or to those cues which draw their attention to the 
            
        intact visual field. These are both diffuse cues and one invalid cue. We have 
            
        demonstrated the same deficit in the monkey after surgical removal of cortical 
            
        area 7. This allows us to study directly a region of cortex in the monkey which 
            
        is critical for visual spatial attention. Normal human controls or patients with 
            
        temporal lobe damage do not have these problems. Humans with Alzheimer s demen- 
            
        tia are extremely slow in all aspects of this task. Males with idiopathic hypo- 
            
        gonadotropic hypogonadism have unusual patterns of responding on our attention 
            
        task; they are slow in responding to all targets in their right visual field, 
            
        independent of the preceding cue. They are also slow in responding to targets 
            
        after diffuse cues. 
            
         
            
        These studies have helped to localize an area of the brain, the inferior parietal 
            
        lobule, which is critical for visual spatial attention and helped to clarify its 
            
        contribution to this cognitive process. In addition they have demonstrated a 
            
        possible endocrine influence on visual behavior. 
            
         
            
        DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
            
        NOTICE OF INTRAMURAL RESEARCH PROJECT 
            
         
            
        PERIOD COVERED 
            
         
            
        October 1, 1985, to September 30, 1986 
            
         
            
        PROJECT NUMBER 
            
         
            
        ZOl EY 00109-06 LSR 
            
         
            
        TITLE OF PROJECT (80 ctwacitn v lets Tttit must tn or ont hnt b»tw»»n tfie txyMrs ) 
            
         
            
        Visual Motion Processing in the Primate Brain 
            
         
            
        PRINCIPAL INVESTIGATOR (Usi otntt prolaiitonU panonnti fietow th» Pnncipai Invtsugtiv ) (Nvn», BM. taoorarcyy antf vxMurt aAMDon; 
            
         
            
        PI: Robert H. Wurtz 
            
         
            
        Others:. Max R. Dursteler 
            
        Hidehiko KonatBu 
            
        Dwayne S. Yamasaki 
            
         
            
        Ph.D. Chief 
            
         
            
        M.D. Visiting Scientist 
            
         
            
        Ph.D. Visiting Scientist 
            
         
            
        Ph.D. Guest Researcher 
            
         
            
        LSR, NEI 
            
         
            
        LSR, NEI 
            
         
            
        LSR, NEI 
            
         
            
        LSR, NEI 
            
         
            
        COOPERATING UNITS (It any) 
            
         
            
        LAB/BRANCH 
            
         
            
        Laboratory of Sensorimotor Research 
            
         
            
        SECTION 
            
         
            
        Visuomotor Integration Section 
            
         
            
        INSTITUTE AND LOCATION 
            
         
            
        NEI, NIH, Bethesda, Maryland 20892 
            
         
            
        TOTAL MAN- YEARS 
            
         
            
        4.8 
            
         
            
        PROFESSIONAL 
            
         
            
        2.8 
            
         
            
        OTHER 
            
         
            
        2.0 
            
         
            
        CHECK APPROPRIATE BOX(ES) 
            
         
            
        D (a) Human subjects 
            
        C (a1) Minors 
            
        D (a2) Interviews 
            
         
            
        D (b) Hunnan tissues X (c) Neither 
            
         
            
        SUMMARY OF WORK (Use slanOarO unreduced type Do not exceed We space provided I 
            
         
            
        Visual motion processing in the cerebral cortex of the monkey is carried out in a 
            
        series of specialized areas. We have previously investigated one of these areas, 
            
        the middle temporal area (MT) and we have now explored the next area, the medial 
            
        superior temporal area (MST). We investigated the relation of motion processing 
            
        to the generation of an eye movement that is dependent on such motion processing, 
            
        smooth pursuit eye movements. We found cells that discharge during pursuit eye 
            
        movements fell into two groups. Those that were dependent upon visual stimula- 
            
        tion lie in the foveal region of MT and lateral MST, while those related to the 
            
        movement itself were in the lateral and dorsal MST. Punctate removal of cells in 
            
        these areas of MST using a neurotoxin, ibotenic acid, shoved a deficit in pursuit 
            
        initiation for targets moving in the contralateral visual field (a retinotopic 
            
        deficit) and a deficit in maintenance of pursuit as long as the target was moving 
            
        toward the side of the lesion (a directional deficit). We interpret the visual 
            
        response of cells in MT and the retinotopic deficit as being related to visual 
            
        stimulation (retinal slip) and the pursuit related cells and the directional 
            
        deficit as being related to an efference copy signal of pursuit eye movements. 
            
         
            
        I 
            
         
            
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        National Ins:.ru:e3 of a 
            
        Bethesda, Md. 20392" 
            
         
            
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        l|^ Amazing R«3« 
            
        Amaztng Help. 
            
         
            
        http://nihlibrary.nih.gov 
            
         
            
        10 Center Drive 
            
         
            
        Belhesda, MD 20892-1150 
            
         
            
        301-496-1080 
            
         
            
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