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Full text of "Annual report"

I 



/^ DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 

ZOl EY 00003-15 IMDD 



'ERIOD COVERED 



October 1, 1986 to Sqprterrber 30, 1987 



riTLE OF PROJECT (60 chartcfen or less Title must tit on one line between the toniers ) 

RTcirnacology of Oculau: CJcrplicatians 

'RINCIPAL INVESTIGATOR (Ust ottier professional personnel below ttte Principal Investigator ) (Name, title, laboratory, and institute aflihation) 

PI: Peter F. Kador Ri.D. Research Chemist IMOD, NEI 



Others: Yoshio Akagi 
Sanai Sato 
Tsuyoshi Tarmnoto 
Gurley, Rebecxa 
Katrina Anristrong 



M.D. Fh.D. Visiting Scientist 
M.D. Visiting Associate 
Ri.D. Visiting Scientist 
M.S. Biologist 
B.A. Guest Worker 



OOPERATING UNITS (H any) 



None 



>B/BRANCI- 



laboratory of Mechanisms of Oculeir Disease 



SECTION 



Sectican of Molecular Fharmaoology 



NSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



OTAL MAN-YEARS 



5.5 



PROFESSIONAL: 



4.0 



OTHER 



1.5 



:hECK APPROPRIATE BOX(ES) 

Zl (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



tUMUARY OF WORK (Use standard unreduced type Do not exceed ttw space provided ) 



Ihe events leading to the onset of various ocular complications are being studied 
inaddition to nethods for their potential phannacolo^ical contr ol. 
Z^^^Y^^Il ^ relationships between the enzymes aldose reductase and aldehyde 
^iP.^v^V°?r^^ °^ retincpathy, catar act, p^il functio n andflS^ 
changes, and keratopathy induced by diabetes or galactose mia are being 
investigated. Methods for either delaying or preventing the onset of these 
Sl^'°^ ^^""""^ ^ phamacological control of these enzymes are also beir^ 

^.>^^?^^'^^'T^^°" °^ ^^^ ^^'P^ °f cataracts are also be/jig studied 
^^well^ methods for cxjntrolling their onset through p^^arrracological 



H^ 



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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 

Z01 EY 00011-13 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 characters or less Title must fit on one Ime betweer) the borders.) 

Pigment Dispersion With and Without Glaucoma 



PRINCIPAL INVESTIGATOR (Ust other prolessiortal personnel below the Principal Investigator ) (Name, title, laboratory, and institute afliliation) 



PI; 



Others: 



Muriel I. Kaiser-Kupfer M.D. 



Head, Section on Ophthalmic CB, NEI 
Genetics and Pediatric 
Ophthalmology 



Carl Kupfer 
Lessie McCain 
Sandeep Jain 



M.D. 
R.N. 
M.D. 



Director 

Clinical Technician 

Visiting Fellow 



NEI 
CB, NEI 
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 

1.35 



PROFESSIONAL: 



1.25 



OTHER: 



.1 



CHECK APPROPRIATE BOX(ES) 

D (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 ) 



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 disease. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00015-22 LRCMB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 characters or less Title must fit on one line between the borders.) 

The Cell Biology of the Vertebrate Retina 



PRINCIPAL INVESTIGATOR (Ust other professional personnel below the Principal Investigator ) (Name, title, latxiralory. and institute affiliation) 



PI; 



Paul J. O'Brien 



Others: Robert St. Jules 



Ph.D. 



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 



0.0 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues E (c) Neither 



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided ) 

The post-translational modifications of rhodopsin include acylatlon, glycosylation 
and chromophore addition. All appear to take place in the rod inner segment. The 
resulting molecules exhibit a slightly higher molecular weight than the mature 
rhodopsin in the outer segment and thus can be distinguished. The role of the 
palmitate residues is unknown but could be related to membrane assembly. The 
addition of the vitamin A chromophore seems to be essential for intracellular 
transport of the opsin protein to the Golgi and to the outer segments. The 
addition of galactose residues may be a requirement for normal outer segment disc 
formation as it appears to be present only in the rhodopsin molecules found in the 
plasma membrane and basal folds. 

The polyphosphoinositide pathway has been detected in rat rod outer segments thus 
extending the known distribution of this pathway from invertebrates and cold- 
blooded vertebrates to warm-blooded vertebrates. The role of this pathway in 
either transduction or light adaptation may be universal. 

A manganese-dependent 5 '-nucleotidase that cleaves cytidine monophosphate has been 
found to become highly active In rod outer segment tips at the time of disc 
shedding. It has been isolated, partially purified and characterized and could 
provide insight into new mechanisms related to the shedding process. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



J01 EY 00016-20 LRCMB 



I 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE Of PROJECT (BO cfmracnrz or mss 77n* must tn or on* Imt Omtwttn trm 6oaMfl.> 

The Biochemistry of Normal and Dystrophic Retinas 



PRINCIPAL INVESTIGATOR fL/lI offwf prolastion»l personnel Otiow m» PnncipH Ini/tstigttof ) (Namt. tm». laDorttory, mm} msmam tftumtion) 



Pi! 



Paul J. O'Brien 



Ph.D. Head, Section on 

Cell Biology 



LRCMB, NEI 



COOPERATING UNITS (K any) 



School Of Veterinary Medicine, University of Pennsylvania (G. Aguirre) 



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; 

0.2 



PROFESSIONAL; 



0.2 



OTHER: 



n.n 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues 13 (c) Neither 



SUMMARY OF WORK (Ust ttvxive unrwaucuO lypt Do not »tc—<l the ipac* prwiota.) 

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 intravltreal 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 
intravltreal 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. The evidence suggests a significant 
diminution in the esterif icatlon of palmitic acid but not of arachidonlc acid. 
Moreover, glycerol incorporation into phospholipid is not decreased in the affected 
animals, thus the defect may specifically involve palmitate. 



^ttUatAdaaMmiM^ 



G'O (I*-*!* 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



ZOl EY 00045-09 LSR 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



TITLE OF PROJECT (80 characters or less Title must lit on one line between the borders.) 

Visuomotor Properties of Neurons in the Thalamus 



PRINCIPAL INVESTIGATOR (Ust other prolessional personnel t>elow the Phncipal Investigator ) (Name, title, laboratory, and institute affiliation) 



PI: David Lee Robinson Ph.D. 

Others: John W. McClurkin Ph.D. 

Caroline Kertzman Ph.D. 

Irene Letvin M.D. 

Edmond FitzGibbon M.D. 

Lance M. Optican Ph.D. 

Barry J. Richmond M. D. 

Timothy Gawne Ph.D. 



Research Physiologist LSR NEI 

Guest Worker LSR NEI 

IRTA LSR NEI 

Clinical Fellow NINCDS 

Clinical Fellow LSR NEI 

Research Engineer LSR NEI 

Senior Surgeon, PHS LNP NIMH 

Physiologist LNP NIMH 



COOPERATING UNITS (if any) 



LAB/BRANCH 

Laboratory of Sensorimotor Research 



SECTION 

Visuomotor Integration Section 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20205 



TOTAL MAN- YEARS: 

2.2 



PROFESSIONAL: 



1.0 



OTHER: 



1.2 



CHECK APPROPRIATE BOX(ES) 

K (a) Human subjects 
D (a1) Minors 
n (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided ) 

We studied the responses of neurons to stimulus movement: that generated by real 
motion in the environment, by saccadic eye movements, and by smooth pursuit eye 
movements. Cells in the pulvinar discharge to real movement during periods of 
fixation but not when a saccadic eye movement causes the visual stimulation. 
However, these same cells do respond to the visual stimulation induced with pur- 
suit eye movements. Many of these cells have a pause in their activity when an 
animal makes eye movements in total darkness, and it may be this inhibitory pro- 
cess which prevents them from responding with eye movements in the light. Neu- 
rons in the lateral geniculate nucleus respond in all three conditions: during 
fixation and with both types of eye movements. Cells in the superior colliculus 
are similar to those in the pulvinar, they respond to real motion during fixation 
and with pursuit movements but not with saccadic eye movements. These data show 
that some parts of the brain are influenced by the behavioral context in which 
visual stimulation occurs whereas others are not. We tested other pulvinar cells 
for their excitability after saccadic eye movements. Many respond better to 
light just after an eye movement than during fixation. Such changes may be 
related to the analysis of new data with each change in eye position. Other pul- 
vinar cells are very selective for the frequency of stroboscopic stimulation; 
they respond very strongly to pulses at 4 to 6 per second. Frequently, they 
respond better to later stimuli in a train than to the first stimulus. Cells in 
the lateral geniculate nucleus have a wide variety of temporal response patterns 
which encode the details of visual stimulus patterns. Normal humans respond fas- 
ter to a visual target when its spatial location is correctly indicated by a 
cuing light than when the location is incorrectly cued. The hypothesis is that 
the cue draws attention to its location and thereby facilitates reaction times. 
Patients with progressive supranuclear palsy who cannot make vertical eye move- 
ments are nonetheless able to move their attention in that direction. 






'^*«,^ r,c.. 



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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



ZOl EY 00049-09 LSR 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



TITLE OF PROJECT (80 characters or less We must tit on one ftne between tt>e borxlers.) 

Cerebral Cortical Mechanisms for Eye Itovements and Visual Attention 



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator j (Name, title, laboratory, and institute affiliation) 

PI: Michael E. Goldberg M.D. Chief, NMS LSR, NEI 



Others: Mark A. Segraves Ph.D. 

Rolf Boch Ph.D. 

Edmond J. FitzGibbon M.D. 

Gregory B. Stanton Ph.D 



Senior Staff Fellow LSR, NEI 

Visiting Fellow LSR, NEI 

Senior Staff Fellow LSR, NEI 

Guest Researcher LSR, NEI 



COOPERATING UNITS (if any) 



LAB/BRANCH 

Laboratory of Sensorimotor Research 



SECTION 

Neuro-Ophthalmologic Mechanisms Section 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS: 
5.0 



PROFESSIONAL; 

3.0 



OTHER: 



2.0 



CHECK APPROPRIATE BOX(ES) 

H (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.) 

The activity of single neurons in the prefrontal cortex that projects to the 
frontal eye fields has been studied in a number of visual and oculomotor tasks. 
Neurons in this region are visually responsive and show two sorts of activity 
before the beginning of a saccade: presaccadic enhancement and presaccadic reac- 
tivation. These results suggest that the prefrontal cortex participates in the 
planning of visually guided saccades. 

Monkeys trained on a short saccadic adaptation paradigm learn quickly to change 
the amplitude of their saccades. Stimulation of the superior colliculus in the 
short term adapted case yields the same saccades as the unadapted case. The 
activity of some single neurons in the superior colliculus shows evidence of this 
adaptation: When a monkey makes a saccade of adjusted amplitude in response to a 
visual stimulus, some collicular neurons discharge before saccades ordinarily not 
associated with activity from those neurons. These observations were extended to 
a longer-term adaptation paradigm. One or more extraocular muscles were weakened 
by injection of botulinum toxin, and the non-paretic eye masked. The monkeys 
adapted the gain of their eye movements so that the seeing, weak eye made close 
to normal saccades and the non-seeing, normal eye made saccades of much larger 
amplitude than normal. Stimulation of the superior colliculus resulted in the 
production here too of saccades that did not reflect the adaptation process. 

A class of patients with formal reading scores within the normal range who 
nonetheless consider themselves to be poor readers were found to have a higher 
than normal amount of unwanted rapid eye movements (square wave jerks) during 
visual fixation, and a higher than normal amount of backward eye movements during 
reading. Fixational instability did not correlate with performance on a quanti- 
tative assessment of skeletal motor functions which correlates with attentional 
deficit disorder in children. 



I 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00060-09 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO characters or less Title must tit on one lirte between the borOers ) 

Visual Function and Ocular Pigmentation In Albinism 



PRINCIPAL INVESTIGATOR (Usi other prolessK>nal penonrtel below me Principal Investigator ) (Name, title, laboratory, ana institute affiliation) 

PI: Muriel I. Kalser-Kupfer M.D. Head, Section on Ophthalmic 

Genetics and Pediatric 
Ophthalmology 



CB, NEI 



Others: Lessie McCain 
Rafael Caruso 
Doris J. Collie 



R.N. Clinical Technician 
M.D. Visiting Scientist 
A. A. Health Technician 



CB, NEI 
CB, NEI 
CB, NEI 



COOPERATING UNITS (li 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) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaara unreOuceti type Do not exceed the space provioea.) 



Patients with hypomelanotic disorders such as ocular albinism, oculocutaneous 
albinism, Chediak-Higashl disease, Hermansky-Pudlak syndrome, and iris 
transillumination defects are being recruited to determine visual function in 
these conditions and to evaluate its course over time. Family members are 
evaluated to attempt to determine factors which may identify the hetrozygous 
state. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00062-11 CB 



PERIOD COVERED 

October 1 , 1986 to September 30, 1987 



TITLE OF PROJECT (80 chartclen or less Title must In or one line between me botOers.) 

Irido-Corneal-Endothellal (ICE) Syndrome 



PRINCIPAL INVESTIGATOR (Ust other prolessionml personrtel Delow ttte Principal Investigator ) (Name, title, laboratory. anC institute attiUation) 



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 (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: 

.35 



PROFESSIONAL; 



.25 



OTHER: 



.1 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Hunnan tissues D (c) Neither 



SUMMARY OF WORK (Use stanaera unreHuced type. Do not exceed ttte space proviOeO.) 



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. 



■^p" «■■*-»■* 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



ZOl EY 00065-10 OSD 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



TITLE OF PROJECT (80 cfttracMrz or l»ss TiOt must ht on orn lint between the bomert.) 

Physiological studies of the Primate Visual System 



PRINCIPAL INVESTIGATOR (List ottier proteujonti personnel below the Pnncipel lnv9St)gator) (Name, title, leboretory. erxJ mstnute ethuatiofi) 



PI: 



Others: 



Francisco M. de Monasterio, M.D., D.Sc. Medical Officer OSD, NEI 



Edna P. McCrane 



B.S. 



Biologist 



OSD, NEI 



COOPERATING UNITS (» any) 

Lions of District 22C Eye Bank and Research Foundation, Inc (Seabrook, Maryland), 



LAB/BRANCH 

Office of the Scientific Director 



SECTION 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS; 



1.00 



PROFESSIONAL; 



0.50 



OTHER; 



0.50 



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 stenOerti unreduced type Do not exceed the spece provided.) 

This project Involves the study of the physiological organization of neurons of 
the visual system of primates. We have completed a study of the variation of 
functional properties of macaque ganglion cells with Increasing eccentricity, 
which shows that color-opponent ganglion cells form a heterogenous group with 
respect to both spectral and non-spectral cell properties. The receptive-field 
size variation of these cells will be compared with dendritic-field variation of 
Golgi-impregnated ganglion cells, to assess If physiological differences reflect 
anatomical differences. In a separate study, we are comparing published data on 
the decline of human visual acuity with Increasing eccentricity with the decline 
of cone and ganglion cell densities (cells/sq. degree) at various eccentricities 
of the retina of human donor eyes. Finally, we are completing analyses of prior 
studies for their publication. 



""" '"■* '°— •—■■ 



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DEPARTMENT OP HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



ZOl EY 00069-10 LI 



PERIOD COVERED 
October 1, 1986 to September 30. 1987 



TITLE OP PROJECT (BO cfttfcnrt c mu Tnm must trt on ont unt omrw»n me txtrvmn.) 

Immune Responses to Ocular Antigens 



PRINCIPAL INVESTIGATOR ILat otrmr pratunnai p»rtonn»i oiow tn» fmcipai tnnsiigamr ) (Sam*, ont. luxxutofy, »na mtmut* tffmaoon) 

PI: Igal Gery Ph.D. 



Others: Shigeto Hirose M.D. 

Hiroki Sanui M.D. 

Takao Tanaka M.D. 

LiHong Hu M.D. 

-Roberto de Bara M.D. 



Head, Section on Experimental 
Immunology 

Visiting Fellow 
Visiting Fellow 
Visiting Fellow 
Visiting Fellow 
Senior Staff Fellow 



LI, NEI 



LI, NEI 

LI, NEI 

LI, NEI 

LI, NEI 
LI, NEI 



COOPERATING UNITS (H any) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION _ 
Section on Experimental Immunology 



INSTITLITE AND LOCATION 

NIH, NEI, Bethesda, Maryland 20892 



TOTAL MAN- YEARS; 
7.95 



PROFESSIONAL; 



7. 84 



OTHER. 



0.11 



CHECK APPROPRIATE BOXfES) 

D (a) Human subjects 
D (a1) Minors 
□ (a2) Interviews 



C3 (b) Human tissues D (c) Neither 



SUMMARY OF WORK (U»t mnoam unmaucaa rype Do not ameff me tpae* pronome.) 

This project is aimed at learning about the pathogenesis of inflammatory eye 
diseases which are designated "uveitis". In experiments with human material we 
have found that by using a sensitive assay, lymphocytes from a portion of 
healthy donors react in culture to retinal-specific antigens, S-antigen (S-Ag) 
and interphotoreceptor retinoid-binding protein (IRBP) . Furthermore, clones of 
lymphocytes with specificity toward S-Ag were cultivated from the blood of a 
healthy donor. It is proposed that such lymphocytes, when activated, could 
play a pivotal role in the pathogeneis of uveitic conditions. The major seg- 
ment of this project has focused on the animal disease, experimental autoimmune 
uveitis (EAU) , which is considered a model for certain human conditions. Main 
findings: (1) Bovine IRBP is highly uveitogenic in primates, while monkey IRBP 
did not induce EAU at similar doses. Antibodies from monkeys immunized with 
bovine IRBP cross reacted well with monkey IRBP but the cross reaction was 
poorly detected by cellular reactions. (2) Fragments of IRBP of known amino 
acid sequence were found highly uveitogenic in rats, thus making it possible to 
identify the uveitogenic site(s) of this molecule. (3) A cell line of rat 
lymphocytes specific for IRBP was established in culture. The line cells 
produced EAU at numbers as low as 500,000/rat and will be useful for future 
studies on the pathogenesis of this disease. (4) Rats of the W/F inbred strain 
are poor responders to S-Ag induced EAU. This low susceptibility was found to 
be due to a poorly developed cellular immune response to S-Ag. (5) EAU develop 
ment was found to be markedly enhanced by local damage to rat eyes. The data 
suggest that local injury could facilitate immune -mediated inflammation in the 
human eye as well. (6) Animals immunized with IRBP or S-Ag develop pineal- 
itis, in addition to uveitis. The type of inflammation is different, however, 
in the two organs of affected rats and we report here that the "acute" inflam- 
mation in the eye disappears within 10 days while the "chronic" infiltration in 
the pineal lasts for at least 3 months. 



PHC «n.n ,c.., ..^. 



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DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBE3 



ZOl EY 00070-10 LRCMB 



PERIOD COVERED 

October 1. 1986 to September 30. 1987 



TITLE OF PROJECT (80 ctttrtcmn of /•« TiV» must tit on ont lint between th« borxltrt.) 

Vitamin A and Ocular Tissues 



PRINCIPAL INVESTIGATOR (List ott>»r protessiontl personnti below W« Pnncipal Invtstigitor ) (Namt. Of%, ttboratory. tntJ insvtutt iftilittion) 

PI: Barbara Wiggert Ph.D. Head, Section on LRCMB, NEI 

Biochemistry 



Others: 



Ling Lee 


M.S. 


Chemist 


Michael Redmond 


Ph.D. 


Staff Fellow 


Umi Hirose 


M.D. 


Guest Worker 


Gerald J. Chader 


Ph.D. 


Chief 



LRCMB, NEI 

LRCMB, NEI 

LRCMB, NEI 

LRCMB, NEI 



COOPERATING UNITS (» 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; 



2.8 



PROFESSIONAL: 



.^ 



OTHER; 



1-n 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



[1 (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Us» starxSut unnducad typa Do not »*c»u<l tht tpac* pmvidtd.) 

Enzyme-linked immunosorbent assay (ELISA) was used to quantitate interphoto- 
receptor retinoid-binding protein (IRBP) in retinoblastoma tumors and in human 
subretinal fluid (SRF) samples. In retinoblastoma tumors there was a direct 
correlation between the degree of differentiation of the tumors and IRBP 
concentration. Higher concentrations of IRBP were found only in the more recent 
rhegmatogenous detachments, and IRBP was absent from SRF of patients with 
retrolental fibroplasia. Cyanogen bromide peptides from purified bovine IRBP were 
purified by high performance liquid chromatography (HPLC) and several peptides 
were found to produce experimental autoimmune uveitis (EAU) in rats. IRBP was 
shown to be phosphorylated in a crude bovine Interphotoreceptor matrix (IPM) wash, 
and the phosphorylation was of serine and/or threonine residues. Intravitreal 
injection of radiolabeled retinol or fctty acids into frog eyes showed both 
retinol and fatty acids to be bound to IRBP. 



DEPARTMENT Of HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



pROjEC' mumbEh 
ZOl EY 00075-09 LI 



PERIOD COVERED 

October 1. 1986 to September 30, 1987 



TITLE O^ PROJECT (BO cffnamrt or mu Tnm musi tn on ont imt omrwmn m* Oorotrt.) 

Immune Functions in Ocular Diseases of Obscure Etiolo 



g2L 



PRINCIPAL INVESTIGATOR (Ust om»r protmtMJonai partonn*: omiow tr>» Pnnap*! Imusiigaior ) (Maim. vo». mDormmry. ana nttnun attmaoon) 

PI: Robert B. Nussenblatt M.D. Clinical Director 



NEI 



Others: 



Alan G. 



Palestine 


M.D. 


Head, Section on Clinical 
Immunology 


LI, 


NEI 


Chan 


M.D, 


Senior Staff Fellow 


LI, 


NEI 


Leake 


M.S. 


Biologist 


LI, 


NEI 


Hirose 


M.D. 


Visiting Fellow 


LI, 


NEI 



COOPERATING UNITS (II any) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTrrLTTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS; 
0.91 



PROFESSIONAL: 

0.21 



OTHER. 



0.7 



CHECK APPROPRIATE BOX/ES) 

Q (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



Summary op work (Un itanoarv unnauoaa typa. Do not a toa ae me toaoa pr o maae.) 

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, purified uveitogenic soluble antigen (S-antigen) , IRBP of the 
retina, and uveitogenic fractions of the retinal S-antigen 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. The serum from these patients is also being evaluated. 



PROJECT NUMBER 
DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 



NOTICE OF INTRAMURAL RESEARCH PROJECT 



Z01 EY 00078-10 LOP ' 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



TITLE Of PROJECT (BO characnn or l*u Tiut must ht on on» knt Ocrwaan (rw ttorxMn.) 

Histopathology of Human Dystrophies and Degeneration 



PRINCIPAL INVESTIGATOR (Lssx amtr profestional personnel o*/o>v m» Principal Inmtigator ) (Ntmt. OVe. »Dorttoiy. tnO mstnutt iftuiuoon) 

PI: Merlyn M. Rodrigues M.D.,Ph.D. Head, Section on LOP, NEI 

Ophthalmic Pathology 
Others: Joseph Hackett B.S. Biologist LOP, NEI 



COOPERATING UNITS (» any) 

Department of Ophthalmology, University of Iowa, Iowa City 



LAB/BRANCH 

Laboratory of Ophthalmic Pathology 



SECTION 

Section on Ophthalmic Pathology 



INSTITUTE AND LOCATION 



National Eye Institute, NIH, Bethesda, MP 20205 



TOTAL MAN- YEARS: 
0.2 



PROFESSIONAL: 
0.1 



OTHER. 
0.1 



CHECK APPROPRIATE BOX<ES) 

IXI (a) Human subjects G (b) Human tissues D (c) Neither 

D (a1) Minors 
D (a2) Interviews 



SUMMARY OF WORK (Use sttndara unrtaucua ryp* Do not (JrCMtf tht tpact pfxunote.) 

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 iramunohistological stains, transmission electron 
microscopy, and SDS 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 



PERIOD COVERED 

October 1. 1986 to September 30. 1987 



PROJECT NUMBER 



ZOl EY 00083-10 CB 



TITLE OF PROJECT (SO cheracten or less Title must tit on one line between the borOers.) 

Gyrate Atrophy of the Choroid and Retina 



PRINCIPAL INVESTIGATOR (Ust otf>er prolessKyiBl personnel below Itm Prmcipel Investigalor ) (Name, title, laboratory, ana mstnute aflilietion) 

PI: Muriel I. Kaiser-Kupf er M.D. Head, Section on Ophthalmic CB, NEI 

Genetics and Pediatric 
Ophthalmology 



Others: Lessie McCain 
Rafael Caruso 
Kent Hlgglns 



R.N. Clinical Technician 
M.D. Visiting Scientist 
Ph.D. Expert 



CB, NEI 
CB, NEI 
CB, NEI 



COOPERATING UNITS (it any) 

The Howard Hughes Medical Institute Laboratory and the Department of Pediatrics, 
Johns Hopkins University, School of Medicine, Baltimore, Maryland 
(Davi'd L. Valle. M.D.) 



LAB/BRANCH 

Clinical Branch 



SECTION 

Section on Ophthalmic Genetics and Pediatric Ophthalmology 



INSTITUTE AND LOCATION 

NEI. NIH. Bethesda. Maryland 20892 



TOTAL MAN- YEARS 

_Li 



PROFESSIONAL; 



OTHER 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF V^ORK (Use stanaart) unreOuced type Do not exceed me space proviOeci.) 

Patients with gyrate atrophy of the choroid and retina are examined systematical- 
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 pyrldoxine to see if serum concentration of ornithine can be reduced, and, if 
so, the patient will be classified as a "responder," and treatment with pyrldo- 
xine will be continued. Nonresponder and responder patients will be placed on a 
low arglnine, 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 retlnoschisis, are also examined and their courses are compared with 
gyrate atrophy patients. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 

Z01 EY 00084-09 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO characters or less Title must tit on one line between the boroers ) 

Anterior Chamber Anomalies Associated with Glaucoma or Ocular Hypertension 



PRINCIPAL INVESTIGATOR (Usi other prolessional personnel below the Principal Investigator ) (Name, title, laboratory, and mstilute atliliation) 

PI: Carl Kupfer M.D, Director NEI 



Others: Muriel I. Kaiser-Kupfer M.D. 



Lessie McCain 
Manuel B. Datiles 
Paul Edwards 



R.N. 
M.D. 
M.D. 



Head, Section on 

Ophthalmic Genetics 

and Pediatric Ophthalmology 
Clinical Technician 
Visiting Scientist 
Visiting Fellow 



CB, NEI 



CB, NEI 
CB, NEI 
CB, NEI 



COOPERATING UNITS (i1 any) 



LAB/BRANCH 

Clinical Branch 



SECTION 

Section on Ophthalmic Genetics and Pediatric Ophthalmology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS 
0.60 



PROFESSIONAL; 

0.40 



OTHER 



.2 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMAR't' 0^ WOhk lUse stanaa'o unreoucec type Do no: etceec the space p':..iaez ] 



With recent embryological research indicating the role of the neural crest in 
contributing to all connective tissues anterior to the lens epithelium, the 
group of developmental anomalies of the anterior chamber with glaucoma or 
ocular hypertension is being reviewed. 



DEPARTME^^r OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



ZOl EY 00092-09 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE Of PROJECT (BO efrmcmrt or mu Tiv must tn on on* km o»rw»»n me Doroan.) 

HLA, ABO, and B-cell Alloantigens and Ocular Inflammatory Disease 



PRINCIPAL INVESTIGATOR (Lai om»' prvumnai pertormmi b»Km tr>» Pnnap*: Investigator ) (Nemt. on* moorttory. »na nsmw anmanai) 

PI: Robert B. Nussenblatt M.D. Clinical Director NEI 



COOPERATING UNITS (f any) 

Center for Drugs and Biologies, Food and Drug Administration (Kamal Mittal, M.D.) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
0.03 



PROFESSIONAL; 



0.03 



OTHEa 



CHECK APPROPRIATE BOXfES) 

El (a) Human subjects 
D (a1) Minors 
D {a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Us* tanow unrtaocaa type. Do not cxcvac me to»o* prwioae.) 

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. 



m 



e*o 1 1 «**i« 



IBfliBI 



DEPARTMENT OF HEALTH AND HUMAN SERVrCES - RUBUC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBES 

ZOl EY 0009A-09 LI 



PERIOD COVERED 

October 1. 1986 to September 30, 1987 



TITLE Of PROJECT (SO cttartcmrz or ku fitm must tn on oo* on* o»rw»n m* tforomn.) 

Immune Mechanisms In Experimental Autoimmune Uveitis 



PRINCIPAL INVESTIGATOR (Lat omur protmtnonu partonnti D»o» ir» fmapti Inrtttigator ) (Stmt. m» Mooratory. •no msmun tHmaOon) 

Clinical Director 



PI: Robert B. Nussenblatt M.D. 

Others: Alan G. Palestine M.D. 

William Leake M.S. 
Rashid Mahdi 



Head, Section on Clinical 

Immunology 
Biologist 
Biologist 



NEI 

LI, NEI 

LI, NEI 
LI, NEI 



COOPERATING UNITS (* mny) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTn-UTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS; 

0.69 



PROFESSIONAL; 

0.2A 



OTHER. 



0.45 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
O (a1) Minors 
D (a2) Interviews 



D (b) Human tissues lEI (c) Neither 



SUMMARY OF WORK (Un sanow unr*aucoe rype. Do not axcvaO rrw xpaca pronnota.) 

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 immune 
responses measured by the lymphocyte culturing technique. The cyclosporines, a 
family with specific anti-T-activity, have been found to be exceptionally 
effective in protecting rats with EAU. Attempts at local immunosuppressive 
therapy in order to prevent EAU have begun. Topical and periocular CsA have 
been used in order to evaluate its effectiveness in EAU. Newer cyclosporines, 
particularly D&G, 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. An in vitro model of 
specific S-antigen antibody production is being developed. 



PMS 60*0 (Pwv 1/B4I 



CO tl<-*<l 



1 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBUC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT MUMBES 

Z01 EY 00096-09 LOP i 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



TITLE Of PROJECT (80 chtrtcmrt or mss Tim must hi or one lint OanvMn irw borotrs.j 

Clinicopathologic Studies of Human Ocular Diseases 



PRINCIPAL INVESTIGATOR (Usl ointr prolassion*i perzonnti t>»tow tr>» Pnncipal tnvtitigttor j (Namt. me. lalx>ralory. ana msmuta tftiliation) 



PI: Merlyn M. Rodrigues M.D., Ph.D. 

Others: Joseph Hackett B.S. 
Reginald Gaskins 



Head, Section on LOP, NEI 
Ophthalmic Pathology 

Biologist LOP, NEI 

Histologist LOP, NEI 



COOPERATING UNITS (K any) 



LAB/BRANCH 

Laboratory of Ophthalmic Pathology 



SECTION 

Section on Ophthalmic Pathology 



INSTITUTE AND LOCATION 

National Eye Institute, NEI, Bethesda, MD 20205 



TOTAL MAN- YEARS: 


PROFESSIONAL: 




OTHER; 


0.3 


0.2 




0.1 


CHECK APPROPRIATE BOX(ES) 






D (a) Human subjects 


D (b) Human tissues 


[E (c) Neither 


D (a1) Minors 






D (32) Interviews 









SUMMARY OF WORK (Ust sianoarc unraaucaa typa Do not •xcveO m« spaca provioaa.) 

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 ^40 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 

I of argon laser treatment was shown to be ineffective in halting the spread of 

I cytomegalovirus in patients with AIDS. 

Immunohistocheraical 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 



PERIOD COVERED 

October 1, 1986 to September 30, 198? 



PROJECT NUMBER 

Z01 EY 00105-08 LMOD 



TITLE OF PROJECT (80 chartctan or lais T1O9 must ht on ont lint Oarwten ttta bonlars.) 

Structure and Composition of Lens Crystallins with Respect to Cataractogenesis 



PRINCIPAL INVESTIGATOR (Ust of/)»r prt>lassion»l ptrsonnal balow ttia Pnncipal Invastigaior ) (Nama. Vtla. latxyalory, and instnuta aftiliaoon) 

PI: J. Samuel Zigler, Jr. Ph.D. Research Biologist LMOD, NEI 



Others: Valerie A. Lucas 
Qing-ling Huang 
Xinyu Du 



Ph.D. Visiting Fellow 
M.D. Visiting Fellow 
M.D. Visiting Fellow 



LMOD, NEI 
LMOD, NEI 
LMOD, NEI 



COOPERATING UNITS (0 any) 

Jules Stein Eye Institute, UCLA Medical School (J. Horwitz); Department of Chemistrj^, 
Adelphi University (F. Bettelheim); Department of Ophthalmology, University of 
Tennessee (H. M. Jernigan, Jr.) 



LAB/BRANCH 

Laboratory of Mechanisms of Ocular Diseases 



SECTION 

Section on Cataract 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 



2.6 



PROFESSIONAL: 



2.6 



OTHER: 



0.0 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



E] (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Uia standarO unraducad typa Do not ancaad ttia tpaca providad ) 

The crystallins are the basic structural elements of the ocular lens. These 
globular, structural proteins are evolutionarily conservative proteins with 
structures uniquely suited to their functional role, ie, to form highly organized 
and densely packed protein matrices which are optically transparent. Our studies 
are oriented toward elucidation of the mechanisms of cataract development and the 
role of changes either in the structure or the composition of the crystallins in 
opacification of the lens. 

With respect to structural modifications to crystallins, we are particularly 
interested in the modifications induced by oxidative stress since the lens is 
exposed in vivo to an unusual level of such stress. We have previously investi- 
gated the potential effects of the high concentration of H2O2 in the aqueous humor 
on intact lenses in organ culture, finding that H2O2 is toxic whereas stronger but 
short-lived oxidants (free radicals) derived from it show little toxicity when 
produced in the fluids surrounding the lens. In model systems we have now shown 
that when generated intracellularly the reverse is true. H2O2 itself causes 
little damage, but upon conversion to hydroxyl radicals or related species the 
crystallins are rapidly oxidized. Thus not only the oxidizing species, but the 
location in which it is generated is critical in determining its potential for 
producing lens damage. 

We have recently found that zeta-crystallin, a lens protein unique to guinea pigs 
[Which we discovered and partially characterized. Is absent or present in sharply 
reduced amounts in the lenses of guinea pigs with hereditary congenital nuclear 
cataracts. This finding gives us an ideal opportunity to investigate in an animal 
model system the effect of a major change in crystallin composition. 



iMi 



1 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



ZOl EY 00109-07 LSR 



PERIOD COVERED 

October 1, 1986, to September 30. 1987 



TITLE OF PROJECT (80 characters or less Title must fit art one line between ttte borders.) 

Visual Motion Processing in the Primate Brain 



PRINCIPAL INVESTIGATOR (List Other professional personnel below the Principal Investigator ) (Name, title, laboratory, end institute aftiliation) 



PI: Robert H. Wurtz Ph.D. 

Others: Hidehiko Komatsu Ph.D. 

Dwayne S. G. Yamasaki Ph.D. 

Jean-Pierre Roy M.D. Ph.D. 



Chief LSR, NEI 

Visiting Scientist LSR, NEI 

Guest Researcher LSR, NEI 

Guest Researcher LSR, NEI 



COOPERATING UNITS (if any) 



LAB/BRANCH 

Laboratory of Sensorimotor Research 



SECTION 

Visuomotor Integration Section 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS: 

^.0 



PROFESSIONAL: 

2.0 



OTHER: 



2JL 



n (b) Human tissues K (c) Neither 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 

SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided.) 

We have continued our study of visual motion processing in the cerebral cortex. 
Our investigations concentrated on two areas of cortex that are largely devoted 
to motion processing, the middle temporal area (MT) and the medial superior tem- 
poral area (MST). In area MST we investigated the response of cells to motion of 
the visual background as the monkey made a pursuit eye movement. We could iden- 
tify two types of cells. One type responded vigorously to large field stimula- 
tion and this response frequently was synergistic with the pursuit response. 
Another group of cells respond to small moving spots and are largely insensitive 
to motion of the background. In area MT, we have investigated changes in the 
receptive field size of cells adjacent to a region damaged by a neurotoxin that 
impairs the monkey's ability to generate a pursuit eye movement. We found that 
the receptive fields did not expand selectively to cover the area of the visual 
field previously covered by the cells damaged by the neurotoxin. Many cells did, 
however, show an expansion of their field size in all directions. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 

ZOl EY 00114-07 LOP 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



TITLE OF PROJECT (80 characters or less Title must lit on one line befween the borders.) 

Histopathologic Studies of Animal Models of Human Ocular Disease 



PR_INCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator j (Name, title, laboratory, and Institute affiliation) 

Head, Section on LOP, NIH 
Ophthalmic Pathology 
Biologist LOP, NIH 

Research Chemist LVR, NIH 
Chief, Laboratory 
of Vision Research 



PI: Merlyn M, Rodrigues M.D., Ph.D. 

Others: Joseph Hackett B.S. 

Barbara Wiggert Ph.D. 

Geraldn Chader Ph.D. 



COOPERATING UNITS (if any) 



LAB/BRANCH 

Laboratory of Ophthalmic Pathology 



SECTION 

Section on Ophthalmic Pathology 



INSTITUTE AND LOCATION 

National Eye Institute, NIH, Bethesda, MD 20892 



TOTAL MAN-YEARS: 

0.2 



PROFESSIONAL: 
0.1 



OTHER: 
0.1 



CHECK APPROPRIATE BOX(ES) 

B (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.) 

Immur.ocytocheraical 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. 





c 

i 
c 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



ZOl EY 00115-07 LI 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT fBO cfmcnrt or »si Tiu» must tr on on* im* o»iw»»n vm oorvn.l 

Cyclosporine Therapy in Uveitis 

PRINCIPAL INVESTIGATOR (Lttl ormr proitujona! perjonnti osfow tn» Pnnc**/ invmttigMiof ) (Nmrrm. Btw. MoofBrory, •no ntman tlfmaoofij 

PI: Robert B. Nussenblatt M.D. Clinical Director NEI 



Others: Alan G. Palestine M.D. 

Edward J. Holland M.D. 

Roberto de Bara M.D. 

Francois Roberge M.D. 

Richard P. Wetzig M.D. 



Head, Section on Clinical LI, NEI 

Immunology 

Senior Staff Fellow LI, NEI 

Senior Staff Fellow LI, NEI 

Visiting Associate LI, NEI 

Senior Staff Fellow LI, NEI 



COOPERATING UNITS (f any) 



LAB'B RANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN- YEARS: 
1.A9 



PROFESSIONAL; 

1.48 



OTHER; 



0.01 



CHECK APPROPRIATE BOX(ES) 

[El (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



□ (b) Human tissues D (c) Neither 



SUMMARY Of WORK CUM na/toaro unnajotC rypt Do not azcMO tttt Mpaet 

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. 



AM^iMU&a 



6»0 tl«**<> 



DEPARTME^^■ OF HEALTH AND HUMAN SERVICES • PUBUC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 

PEBIOD COVERED 
Octobe r 1, 1986 to September 30, 1987 

TITLE Of PROJECT (80 cnamamn or m*s Tiv must hi on on» unt MrwMn trm Ooivmn.) 

Oculomotor Disorders in Human Subjects 



projEC' mumbe= 

ZOl EY 00117-07 CB 



PRINCIPAL INVESTIGATOR (iat orr»' proltuiona: ptrtonrm: o»tow m* fmapti Innttigttor ) (Ntmt m*. mooratory. ana mimun tltmaoonj 

PI: James Carl M.D. Senior Staff Fellow CB, NEI 



Others: Edmond FitzGibbon M.D. 
Reuben Gellman Ph.D. 



Senior Staff Fellow 
Staff Fellow 



LSR, NEI 
CB, NEI 



COOPERATING UNPrS (» mnyj 



LAB/BRANCH 

Clinical Branch 



SECTION 

Neuro-ophthalmology Section 



INSTrrLTTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN- YEARS: 
1.7 



PROFESSIONAL: 

1.7 



OTHER: 



CHECK APPROPRIATE BOXfES) 

E] (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY Of WORK (Un tmnavc unmaucmc rypt Do not •z»eO tne soac* promote.) 



The continuing emphasis of this project has been to collaborate with the 
Laboratory of Sensorimotor Research in studying oculomotor disorders in human 
subjects. The computerized methods for recording and analysing eye movements 
pioneered by the LSR have been applied to a variety of clinical eye movement 
disorders . 

An ongoing series of experiments established a set of normative values for 
human performance of several of the oculomotor subsystems, particularly the 
saccadic and pursuit systems. The major advances in these areas were 
extensions of neurophysiological work done in the LSR on non-human primates. 
The major findings included a description of the motion processing needed to 
keep the eyes following a moving target by saccades and pursuit movements. The 
human brain requires about 75 milliseconds to begin to follow moving stimuli, 
but an accurate assessment of the stimulus velocity develops over an additional 
100 milliseconds. 

Studies on the role of the basal ganglia in eye movement processing continued 
with a study of patients with progressive supranuclear palsy, with particular 
attention to the abnormalities of vertical eye movements in spite of relatively 
preserved horizontal eye movements. These patients were also examined for 
attentional deficits. 

Additional ongoing projects included following patients with a variety of 
neurological disorders of metabolism such as Gaucher's, Fabry's and 
Niemann-Pick disease. 



PmS 6040 mev i/M) 



c*o t<<-«<* 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



PROJECT NUMBER 



ZOl EY 00122-07 OSD 



TITLE OF PROJECT (80 characMrs (y teM Trtte must tit on one lint between ttie borders ; 

Anatomical Studies of the Primate Visual System 



PRINCIPAL INVESTIGATOR (Ust other prottssiooaJ personnel below the Pnncipal Investigator ) (Name. otle. laboratory, and institute affiliation) 



PI: 

Others: 



Francisco M. de Monasterio, M.D., D.Sc. Medical Officer OSD, NEI 



Edna P. McCrane 
Marvin B. Shapiro 

Catherine J. Szellga 



6.S. 
M.S. 



Biologist 
Research 
Mathematician 
Normal Volunteer 



OSD, NEI 
LSM, DCRT 

CC 



COOPERATING UNITS (If any) 

Howe Laboratory, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 
(Boston, Massachusetts), and Laboratory for Statistical Methodology, DCRT. 



LAB/BRANCH 

Office of the Scientific Director 



SECTION 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS; 



1.20 



PROFESSIONAL: 



0.50 



OTHER: 



0.70 



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 stanOarxi unreduced type Do not exceed the space provided.) 

This project involves the study of the anatomical properties and organization 
of cells in the visual system of primates, with emphasis on the retina and the 
visual cortex. The blue-sensitive cones of the macaque retina were selectively 
labelled using tissue-reactive dyes injected into the vitreous humour, and the 
spatial properties of the retinal point pattern of these cones was examined. We 
have developed a model describing the degree of regularity and structure of the 
cone pattern. To evaluate the topographical relationship between the cones and 
ganglion cells of the area centralis of human and macaque retina, especially in 
the fovea, we have also studied and quantified the radial displacement between 
photoreceptors and postreceptoral cells, and measured the density of both cones 
and ganglion cells. Correction for such displacement permits the topographical 
comparison of the densities of these two cell types in terms of visual angle; 
this comparison allows for an estimate of the overall degree of convergence of 
cones to ganglion cells, and provides boundaries for the areal coverage factor 
of these cells. We have also compared the density of ganglion cells to that of 
cells of the lateral geniculate nucleus (LGN), both for the parvocellular and 
the magnocellular streams; this comparison provides information about central 
magnification properties in this nucleus. 



PHS 6040 (Rev 1/84) 



CPO ti4-e<( 



m 
i 

C 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00123-07-CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 cnaraciers or less Trile must tit on one line between Itte bomers ) 

Clinical Psychophysics of the Visual System 



PRINCIPAL INVESTIGATOR (Usi other prolessionBi personnel Oe/ow me Principal Investigator ) (Name, title. latx>ralory. ana institute atliliationj 



PI: 



Muriel I. Kaiser-Kupfer M.D. 



Others: Rafael C. Caruso 
Kent E. Higgins 
Ralph D. Gunkel 



M.D. 

Ph.D. 

O.D. 



Head, Section on CB, NEI 

Ophthalmic Genetics 
and Pediatric Ophthalmology 

Visiting Scientist CB, NEI 

Expert CB, NEI 

Ophthalmic Physicist CB, NEI 



COOPERATING UNITS (it 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) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stentiaro unreajceO type. Do not exceea trie space proviaed.) 



The visual function of patients 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 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 effect 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 

Z01 EY 0012^-07 LRCMB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO c/i«/«cf»fS Of fss Vtlt must tit on one Una tjetwBtn m« borOen.) 

Metabolism of the Retina and Pigment Epithelium 



PRINCIPAL INVESTIGATOR (Liit othti protessiontl perjonnai fieto* tf>* Pnnapal lnvtst)gttor ) (Namt. rni*. taboratory. and msmuta aftilmtion) 
PT. r.or'sTr^ .1 Phartor- Ph H Th i of LRTMR. NRT 



PI: Gerald J. Chader 

Others: Marlissa Campbell 
Robert Waldbillig 
R. Theodore Fletcher 



Ph.D 



Chief 



Ph.D. 


Staff Fellow 


Ph.D. 


Expert 


M.S. 


Chemist 



LRCMB, NEI 

LRCMB, NEI 

LRCMB, NEI 

LRCMB, NEI 



COOPERATING UNITS (» 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: 



2.2 



PROFESSIONAL; 



2.2 



OTHER: 



0.0 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) interviews 



El (b) Human tissues D (c) Neither 



SUMMARY OP WORK (Usa standard unnducad type Do not atcaad tha apaca profridad.) 

Internal and external messengers have been studied which code for aspects of 
growth, development and function of normal retinal cells and also which affect 
differentiation of retinoblastoma cells in culture. Insulin receptors are present 
in high concentration in normal retinal cells and in retinoblastoma cells 
indicating a role for insulin in retinal function. Also, extracellular matrix 
components such as laminin have been found to affect differentiation of cultured 
human retinoblastoma cells. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00126-06 LMDB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO characters or less Title must lit on one line between the borders) 

Crystallin Genes: Structure, Organization, Expression, and Evolution 



PRINCIPAL INVESTIGATOR (List other prolessional personnel below the Principal Investigator) (Name, title, latMratory, and instrtute affiliation) 

PI: Joram Piatigorsky Ph.D. Chief LMDB, NEI 

Ana B. Chepelinsky 
Graeme J. Wistow 
Cynthia Jaworski 
Diana Parker 
liana Keshet 
Bernd Sommer 



Ph.D. 


Expert 


LMDB, 


NEI 


Ph.D. 


Visiting Associate 


LMDB, 


NEI 


M.S. 


Chemist 


LMDB, 


NEI 


B.A. 


Chemist 


LMDB, 


NEI 


Ph.D. 


Fogarty Fellow 


LMDB, 


NEI 


Ph.D. 


Guest Worker 


LMDB, 


NEI 



COOPERATING UNITS (if any) 



See next page. 



LAB/BRANCH 

Laboratory of Molecular and Developmental Biology 



SECTION 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 



12,6 



PROFESSIONAL 



12.6 



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 (Use standard unreduced type Do not exceed the space provided.) 

We have continued to characterize crystallin gene structure although greater 
emphasis was placed on expression. Sequences have been completed, or nearly 
completed, for the human and chicken oA- and the chicken BBl -crystallin genes. 
Intron 1 of the human aA-crystallin gene has been shown to encode an insert 
exon found so far only in rodents. The 5' flanking sequence of the murine 
aA-crystallin gene has been dissected into a distal, enhancer-like element and 
a proximal element. Both elements bind specifically to different nuclear 
proteins of embryonic lens cells, as judged by gel retardation experiments. 
Transfection studies using the pSVOCAT expression plasmid have shown that the 
5' flanking sequence of the chicken 61 -crystallin gene contains an upstream 
region (-603 to -120) that appears to down-regulate promoter activity. Strong 
promoter activity has been identified in the 5' flanking sequence of the 
chicken 6B1 -crystallin gene, initiating our efforts to study the regulation of 
this class of crystallins. The human and murine aB-crystallin genes have been 
isolated; the promoter has been identified in the murine gene. A transgenic 
mouse facility has been established, and several progeny carrying hybrid genes 
using crystallin promoters have been born. Numerous crystallins have been 
shown to be enzymes: e-crystallin is lactate dehydrogenase, 6-crystallin is 
argininosuccinate lyase and T-crystallin is enolase, indicating the pragmatism 
of lens evolution, i.e., the use of enzymatic proteins in a new structural 
role. Finally three crystallin polypeptides have been identified in the 
jellyfish lens; one (35K) has been purified and partially sequenced. 



PHS 6040 (Rev 1/84) 



6PO 9l4>Blt 



t 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00127-11 LMDB 



PERIOD COVERED 

October 1, 1986 to September 30, 198? 



TITLE OF PROJECT (80 characters or less Title must fit on one Ime between the borders ) 

Plasma Membrane Composition and Biosynthesis in Chick Lens Fibers and Epithelia 



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator ) (Name, title, laboratory, and institute afliliationj 

PI: Peggy Zelenka Ph.D. Geneticist LMDB, NEI 



Luke Pallansch 
John Talian 



Ph.D. Staff Fellow 
Ph.D. IRTA Fellow 



LMDB, NEI 
LMDB, NEI 



COOPERATING UNITS (it any) 

Flora de Pablo 
Paul Russell 
David Beebe 



M.D. Diabetes Branch/NIDDK 

Ph.D. LMOD, NEI 

Ph.D. USUHS, Bethesda, MD 



LAB/BRANCH 

Laboratory of Molecular and Development Biology 



SECTION 

Section on Cellular Differentiation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS; 



2.0 



PROFESSIONAL: 



1.3 



OTHER; 



0.7 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues El (c) Neither 



SUMMARY OF V(/ORK (Use standard unreduced type Do not exceed the space provided.) 

This project seeks to determine whether lens fiber differentiation is associated 
with alterations in plasma membrane lipids or proteins. Previous results have 
indicated that phosphatidlyinositol degradation ceases when lens epithelial 
cells differentiate to form lens fiber cells. Since phosphatidylinositol is 
rich in arachidonic acid, a precursor of prostaglandins and leukotrienes, the 
metabolites of arachidonic acid produced by lens cells are being characterized. 
Comparison of metabolites synthesized before and after the onset of fiber cell 
formation demonstrates that the loss of a lipoxygenase pathway metabolite is 
associated with differentiation and the concommitant increase in c-myc mRNA. 
Plasma membrane proteins being investigated include the insulin and IGF 
receptors, and the membrane associated protein calpactin I. Specific insulin 
and IGF receptors have been demonstrated on both lens epithelial cells and lens 
fiber cells throughout embryonic development; a marked decrease in insulin 
receptors is associated with fiber cell formation. Calpactin I has been shown 
to be a major component of the EDTA extractable protein (EEP) of lens membranes. 
This protein binds both phospholipids and actin, and may thus be involved in 
anchoring the cytoskeleton of the lens to the membrane. 



c 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00132-06 LMDB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (SO characters or less Title must tit on one line between the bottlers ) 

Molecular Biology of Photopigments 



PRINCIPAL INVESTIGATOR (Ust other prolessional personnel ttelow the Principal Investigator ) (Name, title, latxjratory. and institute attiliation) 

PI: Toshimichi Shinohara Ph.D. Head LMDB, NEI 



Others: Masahiko Tsude M.D., Ph.D. 

Benjamin Amaladoss Ph.D. 

Kunihiko Yamaki M.D., Ph.D. 

Viji Singh Ph.D. 



Visiting Fellow 
Visiting Assoc. 
Visiting Fellow 
Visiting Assoc. 



LMDB, NEI 
LMDB, NEI 
LDN, NICHD 
LMDB, NEI 



COOPERATING UNITS (H any) 

Larry Donoso 



M.D., Ph.D. Wills Eye Hospital 
Philadelphia, PA 



LAB/BRANCH 

Laboratory of Molecular and Developmental Biology 



SECTION 

Section on Molecular Biology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 



PROFESSIONAL 



OTHER; 



0.0 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



B (b) Human tissues B (c) Neither 



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided ) 



We have investigated the structure, function, evolution and immunogenic sites of 
the retinal S-antigen (^8 K protein) and its gene. The complete amino acid 
sequences of human, bovine and murine retinal S-antigen have been determined by 
partial protein sequencing and cDNA sequencing. Coding sequences of S-antigen 
cDNAs from human, bovine and murine retinas have approximately 80% similarity. In 
contrast, noncoding sequences of these cDNAs have at most only 30J similarity. 
The polypeptide sequences of S-antigen from human, bovine and murine retinas are 
also very similar (-83$). Immunogenic sites of bovine S-antigen were determined, 
as were two monoclonal antibody binding sites (epitopes) and two uveitopathogenic 
sites (named M and K) using 20 different chemically synthesized oligopeptides. 
The minimum size required for EAU induction was also determined. M peptide was 
12 and K peptide was 20 amino acids long. These small peptides contain all the 
necessary information for the induction of EAU. EAU was also observed following 
the adaptive transfer of T cell lymphocytes from Lewis rats which were previously 
immunized with M peptide, indicating that experimental autoimmune uveitis (EAU) 
induced by M was also a T cell mediated autoimmune response. The clinical and 
histopathologic features of EAU induced with M peptide were similar to those 
developed with native S-antigen. The M12 peptide of S-antigen from humans and 
mice has an identical sequence to that of bovine S-antigen. Searching the NBRF 
data bank revealed no extensive sequence homology between S-antigen and other 
proteins, although some sequence similarity was apparent with a-transducin. 
Interestingly, these include the sites subject to ADP-rlbosylation by petussis 
toxin and the phosphoryl binding sites. 



PHS 6040 (Rev 1/84) 



6PO •<4.»1l 



V 

c 

c 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PERIOD COVERED 

October 1, 1986 to September 30. 1987 



PROJECT NUMBER 



Z01 EY 00135-15 



TITLE OF PROJECT (80 chtrmcfri or Itss Trth must tit on on* lint Ottwten ttm borOft.) 

Biochemistry of Retina and Pigmented Epithelium in Health and Disease 



PRINCIPAL INVESTIGATOR (Ust oth»r proftiiiontJ personnel below th* Pnnapal Investigator j (Nimt. otle. laborttoiy, and mstrtuTa affiliation) 

PI: Helen H. Hess M.D. Medical Officer (Research) DSD. NEI 



COOPERATING UNrrS (» any) 

Veterinary Resources Branch, DRS, NIH 



LAB/BRANCH 



Off ire of the Scientific Director. NEI 



SECTION 



INSTITUTE AND LOCATION 

Natinnsi Fyp Tn<;titiite. NIH. Bethesda. Maryland 20892 



TOTAL MAN-YEARS: 

1,3- 



PROFES5IONAL: 

in 



OTHER; 
JL3. 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Usa standard unreOuced typa Do not atctud tha tpaca provtOtd.) 

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 prevent the mature 
cataracts, and dark-rearing prevents the PSO detectable microscopically. 
Pink-eyed dystrophic rats exposed to constant light of 25 footcandles beginning 
(1) at 20-23 postnatal days or (2) at birth, had histopathological changes similar 
to those in some naturally occurring human posterior subcapsular cataracts (PSC), 
such as in retinitis pigmentosa. Many mature cataracts also occur with cyclic 
light of low intensity at a time when a large amount of rhodopsin debris is 
present. In the RCS dystrophic rat, freed retinal may have a prolonged lifetime 
(owing to slowed conversion of retinal to retinol and to poor regeneration of 
rhodopsin). Freed retinal may act as a photosensitizer to generate singlet 
oxygen, a highly energetic oxidant for polyunsaturated lipids. Prevention of the 
cataracts by dark rearing or by feeding a purified diet with llpid-soluble 
antioxidants (vitamin E, BHT * Beta-carotene) supports the hypothesis of 
lipoperoxi dative damage to the lens. Principles established with this readily 
manipulated animal model may have significance for slowing or preventing human 
iPSC and mature cataracts. 



c 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 001i<i<-06-CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO characters or less Trtie must tit on one Itne between Itte borOers.) 

Clinical Electrophysiology of the Visual System 



PRINCIPAL INVESTIGATOR (Usl otner prolessionBl personnel below the Principal Investigator j (Name, title, laboratory, and institute affiliation) 



PI; 



Muriel I. Kaiser-Kupfer M.D. 



Others: Rafael Caruso 

Kent E. Higgins 
Doris J. Collie 



M.D. 

Ph.D. 

A. A. 



Head, Section on Ophthalmic 
Genetics and Pediatric 
Ophthalmology 

Visiting Scientist 

Expert 

Health Technician 



CB, NEI 



CB, NEI 
CB, NEI 

CB, NRT 



COOPERATING UNITS (if 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) 

D (a) Human subjects 
D (a1) Minors 
D (a2) IntervJev/s 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaerO unreOucea type Do not exceea tne space provoed ) 



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. 



PHS 6040 (Rev 1/841 



i^fiOAMU 



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c 

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DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 

Z01 EY 00148-1^ LRCMB 



PERIOD COVERED 

October 1, 1986 to September 30. 1987 



TITLE OF PROJECT (BO chartctarz or leu 7iM must M on Ont lint Mrween tM bonltrt.) 

Visual Control Mechanisms 



PRINCIPAL INVESTIGATOR (Ust oth»r proltssionti perzonnti Oetow th» Principal Investigator ) (Nama. otta. laboratory, and immuta affiliation) 

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 (» 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 BioloRV 



SECTION 

Section on Gene Regulation 



INSTITUTE AND LOCATION 



NEI. NIH. Bethesda. Maryland 20892 



TOTAL MAN-YEARS: 



.2J_ 



PROFESSIONAL. 



0.7 



OTHER: 



_2^ 



CHECK APPROPRIATE BOX^S) 

D (a) Human subjects 
D (ai) Minors 
n (a2) Interviews 



H] (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Usa standarO unrvducaO lypa Do not axcaad tha tpaca provKJad.) 

It has been shown that cyclic nucleotides (cGMP, cAMP) mediate many of the normal 
functions of the neural retina, especially as related to the visual process. 
Moreover, protein kinases (cAMP-dependent protein kinase, C-kinase) mediate the 
function of these nucleotides as well as transduce other important signals (eg, 
calcium, lipids, etc.). We have evidence that (1) abnormalities in cAMP- 
dependent protein kinase may be Involved in human retinoblastoma, (2) cyclic GMP 
accumulation and distribution is abnormal in photoreceptor cells of an animal 
model of inherited retinal degeneration and (3) C-kinase could be involved in 
normal light/dark mechanisms in the photoreceptor outer segment. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT .MUMBER 



:01 EY 001 ^9-1 ^ LMOD 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 chtrucmrs or mu Tim must ttt on ont Imt Otrwun tht OofOtrt.) 

Ultrastructure and Function of the Cells and Tissues of the Eye 



PRINCIPAL INVESTIGATOR (Usi otttmr prottssional p»rsonr»i Mfow tftt Pnnapul Investigator ) (Ntrrm mm. itborutorg. ana msmuu tftUiatxin) 



PI: W. Gerald Robison, Jr. Ph.D. 



Others: Masao Nagata Ph.D. 

Bruce A. Pfeffer Ph.D. 



Chief, Section on 
Pathophysiology 



LMOD, NEI 



M.D. 



Visiting Associate LMOD, NEI 
Senior Staff Fellow LMOD, NEI 



COOPERATING UNITS (» any) 



LAB/BRANCH 

Laboratory of Mechanisms of Ocular Diseases 



SECTION 

Section on Pathophysioloy 



INSTITUTE AND LOCATION 

NEI. NIH. Bethesda. Maryland 20892 



TOTAL MAN-YEARS: 



PROFESSIONAL: 



_^^ 



OTHER: 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



[1 (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Ust stanoarxl unraaucud typa Do no( a*ca»a tna apaca prov^te.) 

The loss of mural cells from capillary walls is the earliest histopathological 
lesion reported in diabetic retinas. Like several other diabetic complications, 
this lesion appears to be related to aldose reductase activity. Mural cells were 
cultured from capillaries of human retinas. Verification that contaminating cells 
had been removed was made on the basis of the mural cell's distinctive appearance 
in culture, inability to internalize acetylated-low-density lipoprotein, and 
immunoreactivity for muscle actin. Using pure cultures of human mural cells, the 
presence of aldose reductase was demonstrated immunohistochemically with antibodies 
directed against human placental aldose reductase, and aldose reductase activity 
was shown biochemically by monitoring the accumulation of xylitol in cells 
incubated with 30 mM xylose. Bovine and canine as well as human mural cells and 
endothelial cells from retinal capillaries have been grown in cell culture so that 
the role of aldose reductase in alterations of cell structure and function in the 
diabetic state could be studied under chemically defined conditions. Aldose 
reductase inhibitors are useful for studies of the possible prevention of diabetic 
retinopathy. 



PHS 6040 (Rav 1/84) 



6^0 IK.*!! 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



ZOl EY 00152-05 LSR 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



TITLE OF PROJECT (80 characters or less Title must lit on one line between the borders. ) 

Adaptive Changes in Saccadic Innervation 



PRINCIPAL INVESTIGATOR (List other prolessional personnel below the Principal Investigator ) (Name, title, laboratory, and institute affiliation) 



PI: Lance Optican 

Others: Zoi Kapoula 

Paolo Inchingolo 
Michael E. Goldberg 
Edward J. FitzGibbon 



Ph.D. Res. Biomedical Engineer 

Ph.D. Guest Researcher 

Ph.D. Visiting Scientist 

M.D. Chief, NMS 

M.D. Senior staff fellow 



LSR, NEI 

LSR, NEI 

LSR, NEI 

LSR, NEI 

LSR, NEI 



COOPERATING UNITS (if any) 



LAB/BRANCH 

Laboratory of Sensorimotor Research 



SECTION 

Oculomotor Control Section 



INSTITUTE AND LOCATION 

NEI, NIH, Betbesda. 



Maryland 20892 



TOTAL MAN-YEARS; 

1.3 



PROFESSIONAL: 

0.9 



OTHER: 



^A. 



CHECK APPROPRIATE BOX(ES) 

IS (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 ) 

Saccades are the rapid eye movements used to change visual fixation. These eye 
movements are very acurate and end without drift. Our previous experiments have 
shown that the brain controls saccadic accuracy and actively suppresses post- 
saccadic drift by altering the levels of innervation sent to the muscles during 
and after a saccade. The adaptive mechanism for suppression of post-saccadic 
drift is sensitive to optically-imposed post-saccadic retinal slip. Our previous 
work in primates showed that the cerebellum was required for altering the gain 
and time constants of the neural components of saccadic innervation. After abla- 
tion of the midline vermis and fastigial nuclei saccades became hypermetric, and 
the adaptive control of saccadic accuracy was lost. After bilateral flocculec- 
tomy, monkeys developed post-saccadic ocular drift and became insensitive to 
optically-imposed retinal slip. 

The current work studies two aspects of saccadic adaptation. First, we are 
extending the work on post-saccadic drift suppression to human subjects. We have 
already found that human subjects, like monkeys, respond to optically-induced 
post-saccadic slip by developing post-saccadic ocular drift. In addition, this 
mechanism appears binocular, and can not adjust the innervation to the two eyes 
differently. The second study attempts to determine the neural mechanisms under- 
lying adaptive control of saccadic accuracy. By comparing details of the sac- 
cadic waveform before and after adaptation with possible models for saccade gen- 
eration, it can be shown that saccadic accuracy must be controlled upstream from 
the superior colliculus, by changing the size of the saccadic command. Prelim- 
inary evidence suggests that the innervation changes come from a second, parallel 
pathway that contributes to the main visual pathway of the saccade command. 



PHS 6040 (Rev. 1/84) 



OPO 9l«-«1t 



DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



ZOl EY 00153-05 LSR 



PERIOD COVERED 

October 1. 1986. to September 30. 1987 



TITLE OF PROJECT (80 characters or less Title must tit on one line between ttte borders ) 

Adaptive Regulation in Primate Oculomotor System 



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator.) (Name, title, laboratory, and institute affiliation) 



PI: Frederick A. Miles D.Phil 

Others: Hubert Kimmig M.D. 

Urs Schwarz M.D. 

James R. Carl H.D. 

Reuben S. Gellman Ph.D. 



Chief, OCS LSR, NEI 

Visiting Fellow LSR, NEI 

Visiting Fellow LSR, NEI 

Senior Staff Fellow CB, NEI 

Visiting Fellow CB, NEI 



COOPERATING UNITS (if any) 



LAB/BRANCH 

Laboratory of Sensorimotor Research 



SECTION 

Oculomotor Control Section 



INSTITUTE AND LOCATION 

NEI. NIH. Bethesda. Maryland 20892 

TOTAL MAN-YEARS; I PROFESSIONAL; 

2.5 1.0 



OTHER; 



.1^ 



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 unreduced type Do not exceed the space provided) 

Experiments were concerned with the ocular following responses of human subjects 
elicited by transient ramp movements of the visual scene. Such tracking move- 
ments normally aid the stabilization of gaze and thereby help to maintain clear 
vision. Responses were consistent, although varied in form from one subject to 
another. Latencies were invariably short, a typical value with a good stimulus 
being about 75 msec. Tracking was transiently enhanced after saccadic eye move- 
ments, the responses generated in the immediate wake of a saccade being on aver- 
age about twice the amplitude of those generated half a second later: postsac- 
cadic enhancement. A small part of this enhancement was shown to result from the 
visual disturbance created by the antecedent saccade since ocular following 
responses were also slightly enhanced after saccade-like shifts of the scene. 
These saccade-like shifts also elicit transient ocular following responses while 
the visual disturbance associated with real saccades do not, suggesting the 
existence of an extraretinal mechanism that prevents the tracking of saccades. 
Partitioning the scene into separate central and peripheral regions showed that 
en masse movement was not the best stimulus: the inphase motion in the surround 
had a suppressive effect. This indicates that the system has developed some spe- 
cial features to facilitate the tracking of objects. 



-p^ o. .^,m 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - f-UBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



ZOl EY 00162-05 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 

TITLE Of PROJECT (80 chartcte'z Of l»is T/i* must hi on one line between Ittt borxMrs ) 

Vitreous Fluorophotometry 

PRlNClPAt INVESTIGATOR {Liit otfter prottsiion§: pe^jonne' fie/ow ttit Pnncipul Investigator ) (Nemt. We. Itborttory, ana mstnjte afliiiation) 



PI: 



Monique S. Roy 



M.D. 



Visiting Scientist 



CB, NEI 



COOPERATING UNITS frf tny) 



None 



LABBRANCH 

Clinical Branch 



SECTION 

Section on Retinal and Vitreal Diseases 



INSTITUTE AND LOCATION 

NE T. NIH. Bethesda. Maryland 20892 



TOTAL MAN-YEARS. 

0.3 



PROFESSIONAL: 

0.3 



OTHER; 
0,00 



CHECK APPROPRIATE BOX(ES) 

S (a) Human subjects 
□ (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaara unreOucea type Do not axcvvO ttie space fyvnOeO ) 

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. 



PhS 60*0 (R»v 1/6*1 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00163-05 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO cnaraciers or less Title must til on one line between trte borOers ) 

NIH Interlnstltute Medical Genetics Program: The Genetics Clinic 



PRINCIPAL INVESTIGATOR (Ust ott>er professional personnel Oelow ffte Principal Investigator ) (Name, title. latx>ratory ana mstnute atlilialion) 



PI: 



Muriel I. Kaiser-Kupfer M.D. 



Others: Lessie McCain 



R.N. 



Head, Section on Ophthalmic CB, NEI 
Genetics and Pediatric 
Ophthalmology 

Clinical Technician CB, NEI 



COOPERATING UNITS (rl any) 



LAB/BRANCH 

Clinical Branch 



SECTION 

Section on Ophthalmic Genetics and Pediatric Ophthalmology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS 
.15 



PROFESSIONAL 



.1 



OTHER 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanoara unreouceO type Do not exceed tne space provioeti j 



The Interinstitute Medical Genetics Program and the Genetics Clinic, supported 
by the Clinical Center, offer a multidisciplinary approach to patients with 
genetic disease (Z01 CP 05139-0^4 CEB). Involved in the program are researchers 
from all Institutes. Patients evaluated in the clinic reporsent a broad spectrum 
of genetic disease. During the last year, approximately ^25 individuals were 
seen, representing approximately 100 different disease categories. Due to the 
high frequency of ocular involvement in many of the cases, almost all the patient 
were evaluated by Clinical Branch staff of were discussed in consultation. The 
Clinic serves as a source of interesting case material concerning patients with 
Inherited or developmental 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 ^u^'BES 



ZOl EY 00172-05 CB 



'ERiOD COVERED 

October 1, 1986 to September 30. 1987 

■|TL£ OF PROJECT (BO cfttrtzttr) c Zeis Titit must lit on one line tmrwten m» borOtri ) 

Senile Macular Degeneration 

>BINCIPAL INVESTIGATOR (Jjsl other proftsnonti personnel belo* the Pnncipel Investigator ) (Heme, title, leboretoiy, »nij msttute etfiliation) 

PI: Muriel I. Kaiser-Kupfer M.D. Head, Section on CB, NET 



Others: Carl Kupfer 

Monique S. Roy 



M.D. 
M.D. 



Head, Section on 
Ophthalmic Genetics 

Director 

Visiting Scientist 



NEI 
CB, NEI 



OOPERATING UNITS (* any) 



None 



AaBRANCH 

Clinical Branch 



SECTION 



Section on Ophthalmic Genetics and Pediatric Ophthalmology 



NSTITUTE AND LOCATION 

NEI. NIH. Bethesda. Maryland 20892 



rOTAL MAN-YEARS. 
Ji2 



PROFESSIONAL: 



Jil. 



OTHER. 



:mECK APPROPRIATE BOX(ES) 

S] (a) Human subjects 
Q (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaera unreOuced type Do not etceea the spec* provtOaa) 

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 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. 



PmS 6040 (R»v \lh*) 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



PROJECT NUMBER 

ZOl EY 00184-05 LI 



TITLE OF PROJECT (80 characttrs or lets Title must ht on one line between the bonien.) 
Cellular Mechanisms in Uveitis 



PRINCIPAL INVESTIGATOR (List other protess^onal personnel below tM Pnnapal Investigator ) (Name. otle. laboratory, and institute atfiimtxinj 
PI: Rachel Caspi Ph.D. Visiting Associate LI, NEI 



Others: Robert B. Nussenblatt 
Francois Roberge 
Chi-Chao Chan 
William Leake 
Myung Kim 
Makoto Higuchi 



M.D. 


Clinical Director 


M.D. 


Visiting Associate 


M.D. 


Senior Staff Fellow 


M.S. 


Biologist 


M.D. 


Visiting Fellow 


M.D. 


Visiting Fellow 



NEI 
LI, NEI 
LI, NEI 
LI, NEI 
LI, NEI 
LI, NEI 



COOPERATING UNITS (» any) 



LABaRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS. 



PROFESSIONAL: 

2.04 



OTHER: 



0.04 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



G (b) Human tissues U (c) Neither 



SUMMARY OF WORK (Use starxiare unreOucud type Do not exceed me space pronOed.) 

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. 



DEPARTMEKPr OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00187-OM-CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO characlers or *ss Title must In on one hne between We boftiers.) 

The Effects of Corneal Contact Lenses on the Cornea 



PRINCIPAL INVESTIGATOR (Ust otrter prolessionei personnel Deiow ttte Principal Invesiigalor ) (Name, title, laboratory, and mstitule aliilianonj 

PI: Manuel B. Datiles M.D. Visiting Scientist 



Others: Carl Kupfer M.D. 

Lessie McCain R.N. 

Muriel I. Kaiser-Kupfer M.D. 



Director 

Clinical Technician 

Head, Section on 

Ophthalmic Genetics 

and Pediatric Ophthalmology 



CB, NEI 

NEI 
CB, NEI 
CB, NEI 



COOPERATING UNITS (U any) 



LAB/BRANCH 

Clinical Branch 



SECTION 



Section on Ophthalmic Genetics and Pediatric Ophthalmology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS: 
0.2 



PROFESSIONAL: 
0.10 



OTHER. 
0.1 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use sianOarv unreduced type Do not exceed trie 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 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



PROJECT NUMBER 



Z01 EY 00188-OiJ CB 



TITLE OF PROJECT (BO characters or less Title must tn on one line berweert me borOers j 

Documentation and Monitoring of Opacities in the Human Lens 



PRINCIPAL INVESTIGATOR (Usi otner protessnynal personnel below the Principal Investigator ) (Name, title laboratory, and institute affiliation) 



PI: Manuel B. Datiles M.D. 

Others: Carl Kupfer M.D. 

Robert Sperduto M.D. 

Peter Kador Ph.D. 

Lessie McCain R.N. 



Visiting Scientist CB, NEI 

Director nei 

Head, Epidemiology Branch BEP, NEI 

Head, Section on LMOD, NEI 

Molecular Pharmacology 

Clinical Technician CB, NEI 



COOPERATING UNITS (if any) 

Image Processing and Analysis Laboratory, DCRT, NIH (Benes Trus, Ph.D., Chief) 
Clinical and Diagnostic Trials Section, NCI, NIH (Sylvan Green, M.D.) 
Nuclear Medicine, Clinical Center, NIH (Joseph Frank, M.D.) 



LAB/BRANCH 

Clinical Branch 



SECTION 

Section on Ophthalmic Genetics and Pediatric Ophthalmology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS: 
0.9 



PROFESSIONAL; 
0.7 



OTHER 
0.2 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaerd unreOuced 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), Retroillumi- 
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 presence, progression, or 
regression. 



PHS 6O40 (Rev MM) 



CO •< 4-9ie 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



ZOl EY 00189-OA LMOD 



PERIOD COVERED 

October 1. 1986 to September 30. 1987 



TITLE OF PROJECT (60 chiracttrj or lass T/Oe must M on ona lint batwean ma borxJars.) 

Oxidation of Proteins in Cataractogenesis and Protein Kinases in Lens Function 



PRINCIPAL INVESTIGATOR (Ust othar proftsstonal parsonnal balow tha Pnncpal Invastigamr ) (Nama. Otia. laboratory, ana insmutt affiliation) 

Donita L. Garland, Ph.D. Expert * LMOD, NEI 



COOPERATING UNITS (» 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: 



0.0 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



El (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Usa stanOart unraOucad typa Do not axcaaa tt<a ifiaca proviOaa.) 

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 function of lens proteins. Bovine and human 
lenses were used. The approach taken has been to study the modifications of 
lens proteins after treatment in vitro by mixed function oxidation systems. 
Such treatment of crystallins led to crosslinking, partial degradation, 
charge changes, and production of nontryptophan fluorescence. Similar studies 
are in progress on a human gamma crystallin expressed in mouse L cells; the 
goal is to identify the modified amino acids. Treatment of lens homogenates 
for several days resulted in brown pigment formation, crosslinking, and the 
introduction of carbonyls. The mechanisms of these reactions are being 
studied. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 

Z01 EY OOigS-OiJ LMOD 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE Of PROJECT (80 characters or less Tnie must In on one line between the boiDers j 

Molecular Biology of Hereditary Eye Diseases 



PRINCIPAL INVESTIGATOR (Ust other protessional personnel below the Principal ln\nstigator ) (Name, title, laboratory, ana nstnute afliliation/ 

PI: George Inana 

Others: Carmelann Zintz 
Yoshihiro Hotta 
Lila Inouye 



M.D., Ph.D. 


Section Head 


LMOD, 


NEI 


Ph.D. 


Staff Fellow 


LMOD, 


NEl 


M.D. 


Visiting Associate 


LMOD, 


NEI 


M.D. 


Staff Fellow 


LMOD, 


NEI 



COOPERATING UNITS (H 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 1/2 



PROFESSIONAL 



3 1/2 



OTHER 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviev/s 



H (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use sianOarO unreOuceO type Do not exceed the space proiriaea) 

Ornithine Aminotransferase Deficiency in Gyrate Atrophy: Gyrate atrophy (GA) is a 
blinding, hereditary degenerative disease of the retina and choroid of the eye 
characterized by a generalized deficiency in the mitochondrial enzyme, ornithine 
aminotransferase (OAT). Using the OAT cDNA which we had characterized before, we 
have established the presence of an OAT gene family and mapped the functional OAT 
and other OAT-related gene sequences to chromosomes 10 and X, respectively. 
Restriction fragment length polymorphisms were found in the functional OAT gene 
sequence and in the OAT-related gene sequences on the X-chromosome which may poten- 
tially show a linkage to X-linked retinitis pigmentosa (XLRP) since the locus of 
these sequences is identical to that of the XLRP linkage marker LI. 28. Analysis of 
the OAT gene, mRNA, and protein in GA patients identified a case with a partial 
heterozygous deletion of the OAT gene, no OAT mRNA, and essentially undetectable 
OAT protein. This finding is the first real demonstration of the OAT defect in GA 
at the gene level and establishes the molecular basis of the genetic defect present 
in GA. In order to determine whether our OAT cDNA clone contains all of the 
sequences necessary for expression of active OAT, we have also constructed a 
mammalian expression clone containing the OAT cDNA and expressed it in mouse 
fibroblasts. Ability to express OAT using our cDNA clone in mammalian cells open; 
up the possibility of considering a gene replacement therapy for GA. 

Hereditary Retinoblastoma: Hybrids between Y79 retinoblastoma and NIH3T3 cells 
were previously shown to be non-malignant, confirming the recessiveness of retino- 
blastoma. Variants were isolated among the hybrids that show reversion to malig- 
nant phenotype, suggesting that additional human gene(s) besides the chromosome 13 
gene may be important in the suppression of malignancy in these cells and that pre 
gressive loss of these human genes from the hybrids may result in malignant rever- 
sion. Hybrids were also made between the Y79 retinoblastoma cells and normal human 
fibroblasts, and shown to be n on-malignant, confirming previous results. 

PHS 6040 (Rev 1/M) 



CPO •l4-«lt 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



PROJECT NUMBER 

Z01 EY 00196-OiJ LRCMB 



TITLE OF PROJECT (80 cffrnctars or l»ss Trtlt must ht on on» lint between the txtrOerz.) 

Molecular Genetics of the Eye and Ocular Diseases 



PRINCIPAL INVESTIGATOR (List ottier professional personnel below the Principal Investigator ) (Name, title, laboratory, and msmute affiliation) 

PI: John M. Nickerson Ph.D. Senior Staff Fellow LRCMB, NEI 



Others: Diane Borst Ph.D. 

Shirley Rainier Ph.D. 

T. Michael Redmond Ph.D. 

Adriana Albini Ph.D. 

Lila Inouye M.D. 



IRTA Fellow 
Staff Fellow 
Staff Fellow 
Visiting Associate 
Staff Fellow 



LRCMB, NEI 

LRCMB, NEI 

LRCMB, NEI 

LRCMB, NEI 

LRCMB, NEI 



COOPERATING UNITS (It 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; 



3.7 



PROFESSIONAL: 



3.7 



OTHER: 



0.0 



CHECK APPROPRIATE BOX(ES) 

[1 (a) Human subjects 
n (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK CUM Standard unreduced type Do not exceed the apace provided) 

My laboratory presently is isolating and characterizing recombinant DNA molecules 
necessary for the study of the structure and expression of IRBP (Interphoto- 
receptor Retinoid-Binding Protein). We have cloned many different cDNAs (copies 
of the IRBP messenger RNA) from bovine retina that correspond to ^.8 kb of the 
IRBP mRNA. We have sequenced portions of all of these overlapping cDNA clones and 
have about 3000 bases in continuous sequence. The IRBP mRNA is long (7000 bases) 
and gives only one band on a Northern blot; however, we have evidence that 
suggests that there is sequence heterogeneity near the 3' end of the IRBP mRNA. 
Two authentic cDNA clones show a striking divergence in their sequences, yet 
sequences both 5' and 3' to the divergence are identical. Both sequences in the 
divergence hybridize to one gene clone. Alternative splicing of the IRBP gene 
pi'imary transcript could explain the origin of the. two types of cDNA clones. The 
cDNA sequences have been used to predict the amino acid sequence of the protein. 
These sequences have been helpful in the analysis of the uveitogenic peptides in 
IRBP. The entire gene for bovine IRBP has been cloned. Partial DNA sequence 
analysis of the gene clone has identified the authentic N-terminus, the putative 
initiator methionine codon and a putative signal peptide sequence of the IRBP 
polypeptide. A second different complete bovine IRBP gene has been identified. 
In human, the IRBP gene is on chromosome 10, as determined by in situ hybridi- 
zation of our bovine cDNA probe to human chromosome squashes. This result was 
verified by isolating genomic clones from a human chromosome 10 specific library. 
iWe have screened a human retinal cell cDNA library with the bovine IRBP cDNA probe 
and have identified several large cDNA clones up to ^.5 kb in length for human 
IRBP. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT .\UMBES 



ZOl EY 00198-^04 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 

TITLE OF PROJECT (BO c/i«ricf»ri or Itss TiU* must lit on ont lint fte^^•»•n m» borOtrt) 

Sorbinil Retinopathy Trial 

PRINCIPAL INVESTIGATOR (List otftat profnnonti personnel below me Pnncipe! Invnugttor ) (Hime. tm». leboretory. end msmute effiiittion) 



PI: Monique S. Roy 

Others: Manuel Datiles 
James R. Carl 



M.D. Visiting Scientist CB, NEI 

M.D. Staff Ophthalmologist CB, NEI 
M.D. Senior Staff Fellow CB, NEI 



COOPERATING UNITS (* tny) 

Division of Diabetes, Endocrinology, and Metabolic Diseases, National 
Institute of 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: 



-LJ_ 



CHECK APPROPRIATE B0X(ES) 

H (a) Human subjects D (b) Human tissues D (c) Neither 

a (al) Minors 
D (a2) Interviews 

SUMMARY OF WORK (Use srindartf unreOjced type Do not ezceeO trte spece prvnOeO ) 

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. 



PnS 6040 |R«v 1/64) 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PERIOD COVERED 

October 1, 1986 to September 30, 198? 



PROJECT NUMBER 



Z01 EY 00201-03 LMOD 



TITLE OF PROJECT (80 chtrmctarz or leu rnh musr ftt on ont lint berwaen me bofdtrt.) 

Molecular Biology of Aldose Reductase 



PRINCIPAL INVESTIGATOR (Ust othar prottuionti penonnti below th* Principal lnvtstig»tor ) (Nimt, otl*. laborttory. ana mstitutt athlmtxtn) 

PI: Deborah Carper Ph.D. ' Biologist LMOD, NEI 



Others: Chihiro Nishimura 
Caroline Graham 



M.D. Visiting Associate LMOD, NEI 
B.A. Chemist LMOD. NEI 



COOPERATING UNITS (H any) 

Wistar Institute, 36OI Spruce St., Philadelphia, PA (Dr. Bernard Dietzschold) 



LAB/BRANCH 

Laboratory of Mechanisms of Ocular Diseases 



SECTION 

Section on Cataracts 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 



1.7 



PROFESSIONAL 



1.5 



OTHER: 



.2 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues El (c) Neither 



SUMMARY OF V^ORK (Us» standard unrvducad typa Do not axcaed the ipaca provtOtd ) 

The enzyme, aldose reductase (AR), has been implicated in diabetic complications 
of the nerve, kidney, retina and lens. Currently, a variety of AR inhibitors 
are being tested as a possible new treatment modality for diabetics, although side 
effects are always a concern. In order to study the function and expression of 
AR, we initiated a study on the structure of aldose reductase using peptide and 
DNA sequencing. We have successfully sequenced over 851 of the aldose reductase 
protein. 

Fifteen Xgtil rat lens cDNA clones were Isolated using oligonucleotide probes 
designed from partial amino acid sequence of purified rat lens AR. One of the 
clones gave hybridization with two separate probes and was subsequently sequenced. 
The insert is 1206 bp in length with an open reading frame encoding 284 amino 
acids ( or a molecular size around 32,300 daltons). The sequences from six rat 
lens tryptic and cyanogen bromide-cleaved peptide fragments (totally 128 amino 
acids) are accounted for within the open reading frame of the cDNA insert, 
indicating that this insert encodes rat lens AR. 

The sequence of AR has significant similarity (50$) with both human liver 
aldehyde reductase and frog lens rho crystallin. Local identities as high as 84$ 
were observed. This degree of similarity suggests that all three proteins belong 
to the same superfamily with related structures and evolutionary origins. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 

Z01 EY 00211-02 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO characters or less Tnie must tit on one line between trie tMnters) 

A Double-Masked Controlled Randomized Clinical Trial of Topical Cysteamine 



PRINCIPAL INVESTIGATOR (Ust other prolessional personnel Delow the Prmapal Investigator ) (Name, title, tatxxatory. and institute atlihation) 



PI: 



Others: 



Muriel I. Kaiser-Kupfer M.D, 



Lessie McCain 
Manuel Datiles 



R.N. 

M.D. 



Head, Section on Ophthalmic 
Genetics and Pediatric 
Ophthalmology 

Clinical Technician 
Visiting Scientist 



CB, NEI 



CB, NEI 
CB, NEI 



COOPERATING UNITS (il any) 

Human Genetics Branch, NICHD, National Institutes of Health, Bethesda, Maryland 
(William Gahl, M.D., Ph.D.) 



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 



OTHER 



.1 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaara unreaucea type Do nor etceea me space provKteO ) 

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 thiol which depletes cystine from cells, was 
introduced in the therapy of cystinotic patients. Although patients had 
improved growth and stabilized renal function, there was no noticeable effect 
on the accumulation of corneal crystals. Recent studies showed that corneal 
cells in tissue culture are readily depleted of cystine by the introduction of 
cysteamine, making feasible the use of topical ophthalmic cysteamine to circum- 
vent the humoral route. After appropriate animal studies to test for complica- 
tions which revealed none, we have begun a double-masked clinical trial to test 
the efficacy of topical cysteamine in humans. Twelve patients have thus far been 
enrolled. Three patients have shown significant decrease in the cysteamine tre 
eyes and are now taking drops in both eyes. 



ated 



PHS 6O40 (Rev 1/S4) 



CPO SI«-CII 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00212-02 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 198? 



TITLE OF PROJECT (60 characters or less Title must tit on one line between the borders.) 

Model Program for Collaboration Between Cataract Surgeons and Ophthalmlo Rp^p;.r^ho 



PRINCIPAL INVESTIGATOR <Lisi otner professional personnel Delow me Prmcipal Investigator ) (Name, title, laboratory, and institute atluiation) 



PI; 



Manuel B. Datiles 



M.D. 



Visiting Scientist 



CB, NEI 



Others: Carl Kupfer M.D. 

Muriel I. Kaiser-Kupfer M.D. 



Director neI 

Head, Section on CB, NEI 

Ophthalmic Genetics and 
Pediatric Ophthalmology 



COOPERATING UNITS (if any) 



See next page. 



LAB/BRANCH 

Clinical Branch 



SECTION 



Section on Ophthalmic Genetics and Pediatric Ophthalmology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS 
0.65 



PROFESSIONAL 
0.65 



OTHER 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaarO unreOuced type Do not exceed tne space provided) 



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 



PROjEC' .\uMBE3 



I 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



ZOl EY 00213-02 CB 



TITLE OF PROJECT (80 chartcmrz or <eu Titl* must lit on oni lint between ttte borOers ) 

Sensory and oculomotor contributions to ocular disorder 



PRINCIPAL INVESTIGATOR (Liit of>e' pro'emonMi personnel below the Principal Investigttor ) {Heme. iwe. letxynory. and mstitult afliiiaoon) 



PI: Kent E. Higgins 

Others: Rafael C. Caruso 
• Monique S. Roy 
Francisco de Monasterio 
Robert Nussenblatt 



Ph.D. Expert 

M.D. Visiting Scientist 

M.D. Visiting Scientist 

M.D. Medical Officer 

M.D. Clinical Director 



CB, NEI 

CB, NEI 
CB, NEI 
OSD 
CB, NEI 



COOPERATING UNITS (it any) 



None 



LAB/BRANCH 

Clinical Branch 



SECTION 

Office of the Clinical Director 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
l.A 



PROFESSIONAL: 
1.0 



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 (Use stenOtrO unreCuceC type Do not exceed tt>e space proviOeC) 

Spatial contrast sensitivity was used to assess losses or changes in overall 
visual resolution in patients having a variety of toxic, inf lainmatory, 
degenerative, or congenital retinal and neuro-ophthalmological disorders of 
the visual system. A criterion-free forced-choice physchophysical 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 measurements 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 is under construction. This system is 
intended to permit focal elect roretinography and high resolution microperimetry 
in small, localized regions of a patient's retina. 



Pis 6040 (R»v Mb*) 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT \UMBEB 



ZOl Ey 00214-.02 CB 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 cfiartct»rz or Mu TiU» must til on one line OefwMn mt borOrs ) 

Acquired and Congenital Color Vision Deficiencies; Mechanisms and Diagnosis 



PRINCIPAL INVESTIGATOR (List otttti professiona' personnai below trtt Principal Inrestigato' ) (Hame. Wf». laboratory, ana mstitjta aHiimtion) 

PI: Kent E. Higgins Ph.D. Expert CB, NEI 



Others: Francisco M. deMonasterio M.D. 
Rafael C. Caruso M.D. 

Robert B. Nussenblatt M.D. 



Medical Officer OSD, NEI 
Visiting Scientists CB, NEI 
Clinical Director CB, NEI 



COOPERATING UNITS (H any) 

None 



LA^BRANCH 

Clinical Branch 



SECTION 

Office of the Clinical Director 



INSTITUTE AND LOCATION 

NEI. NIH. Bethesda, Maryland 20892 



TOTAL MAN-YEARS. 
1.1 



PROFESSIONAL: 

1.0 



OTHER: 



0.1 



CHECK APPROPRIATE BOX(ES) 

B (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use stanaarti unreOucad type Do not aMcee<3 O* space proynaeO ) 

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 data for the purpose of designing better 
tests for detecting color defects secondary to ocular disorder. 



PmS 60*0 (Rev VM) 



D 



DEPARTMENT Of HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



P«C^ECT MUMBEr 



ZOl EY 00217-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE OP PROJECT (BO efncnrz of mu Tnm tnun m on on* an* MiwMn m* Oo<t>»r».; 

Lymphocyte Migration in Experimental Autoimmune Uveitis 



PRINCIPAL INVESTIGATOR (Utt otrmr prolttuont! p»rtonn»i o»ow int Pnncjp*! Intmstigtny ) (h»mt, tmt. »Doftoiy ana mtmjt* aflikaaon) 



PI: 



Others: 



Alan G, Palestine 



M.D. 



Head, Section on Clinical LI, NEI 
Immunology 



Robert B. Nussenblatt M.D. 
Consuelo Muellenberg-Coulombre 

Myung Kim M.D, 

Susan Lightman M.D. 



Clinical Director 
Chemist 

Visiting Fellow 
Visiting Fellow 



NEI 
LI, NEI 
LI, NEI 
LI, NEI 



COOPERATING UNITS (f mny) 



LASmRANCH 

Laboratory of Immunology 



SECTION 

Section on Clinical Immunology 



INSTTT JTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
0.30 



PROFESSIONAL: 

0.20 



OTHER 



iLX 



CHECK APPROPRIATE BOXfES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues E (c) Neither 



SUMMARY OF WORK (Un stmnow unrwauote ryp* Do nol azcMC me MPaca pnxnoue.) 

Experimental autoimmune uveitis (EAU) is induced by immunization of rats and 
other experimental animals with S-antigen (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. Cells from an S-Ag specific T cell 
line migrate into the retina and cause EAU. The kinetics of this migration are 
being studied. S-antigen specific cells reach the eye in greater numbers if the 
inflammation in the eye is induced by S-antigen than if it is induced by another 
mechanism. 



PHS 6040 (Rev 1/641 



c^o ti tf*ei* 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



P«OjECT MjMBE" 

ZOl EY 00218-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 Ofrtcnri or mu Titm must hr on on» tnt o»rw9»n m* oorvrt.) 

Acquired Immune Deficiency Syndrome 



PRINCIPAL INVESTIGATOR ILai otrwr prottunnMi parsonntl oaow in* frtnaoai Invttigtror ) (N»m%. OD*. moorttoiy. ana nimun tflmtoofi) 

PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 

Immunology 



Others: 



Robert B. Nussenblatt 



M.D. 



Clinical Director 



NEI 



COOPERATING UNITS (n 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 Nasur, M.D.); Laboratory of Tumor Cell Biology, National 



LABm RANCH 

Laboratory of Immunology 



SECTION 

Section on Clinical Immunology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS; 
0.09 



PROFESSIONAL; 

0.09 



OTHER; 



CHECK APPROPRIATE BOWES) 

El (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Uwi ttanaw unrwoiXXO type Do not axcveo me aoac* p^ wi ata.) 

Cytomegalovirus retinitis is the major cause of blindness in AIDS patients. 
Although we have previously shown that DHPG is effective in treating this 
infection, the disease relapses without continued maintenance. Maintenance 
therapy requires intravenous infusion and is associated with marrow toxicity. A 
multi-center randomized trial is currently being planned to evaluate the use of 
this drug. 



PmS wvirxt... ■"'"■ 



C»0 •! S'^M 



DEPARTMENT Of HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 

PERIOD COVERED 
October 1, 1986 to September 30, 1987 

TITLE OF PROJECT (80 cf»r»cmrz or mu TttM nual tn on on* imt tmtwtmn in* ooromn.) 

The Effect of Bromocriptine on Human Uveitis 



PROJECT MUMBE" 

ZOl EY 00219-02 LI 



PRINCIPAL INVESTIGATOR (Lat om»' prottiMionti (mrtonnt: o»K>w tn* fnnapai Imtstigimr ) (Ntmi, dm. mocnmfy. ana mmjf tthimoon) 
PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 

Immunology 



Others: Robert B. Nussenblatt M.D. 

Janet L. Davis M.D. 

David C. Herman M.D. 

Jeffrey C. Bloom M.D. 



Clinical Director 
Senior Staff Fellow 
Senior Staff Fellow 
Senior Staff Fellow 



NEI 
LI, NEI 
LI, NEI 
LI, NEI 



COOPERATING UNfTS (> any) 

Metabolism Branch, National Cancer Institute (Marie C. Gelato, M.D.) 



LAB/BRANCH 

Laboratory of Iraniunology 



SECTION 

Section on Clinical Immunology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
1.01 



PROFESSIONAL; 

1.01 



OTHER; 



CHECK APPROPRIATE BOXfES) 

SI (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY Of WORK (Utt sanoaw unrwotjctc lype. Do no! azoMO me Mpaca promotO.) 

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. 

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. 



t^td^^OAtUbm^t—lJA^i. 



CO tl«*«lt 



DEPARTMENT Of HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBES 

ZOl EY 00220-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO cffmcnrt or mu Titf must tn on on» tnt o»iw»en trw ooexmrt.) 

Endocrine Modulation of Immune-Mediated Eye Disease in Rats 

PRINCIPAL INVESTIGATOR (Lat om»' pnHmujonn p»rtonnn 010* tn» frmcofi Invwstivatof j (Iwnt OM. maoramr,. ana nsmjH aflWaoon; 

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. 

Stephanie A. Skolik M.D. 



Chemist 

Visiting Fellow 
Clinical Director 
Research Fellow 



LI, NEI 

LI, NEI 

NEI 

LI, NEI 



COOPERATING UNITS (H urty] 

Metabolism Branch, National Cancer Institute (Marie C. Gelato, M.D.) 



LAfi/B RANCH 

Laboratory of Immunology 



SECTION 

Section on Clinical Immunology 



INSTrrUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN- YEARS; 
1.19 



PROFESSIONAL; 

0.49 



OTHER. 



0.7 



CHECK APPROPRIATE BOX^) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues Q (c) Neither 



SUMMARY OF W^ORK (Urn tmnoarv unrwaucaa typt. Do not trcmtc the Mpaca prwame.) 

In recent years there has been increasing evidence in the literature that 
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 lymphocyte 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. 

The alpha adrenergic antagonist prazosin is also capable of modulating EAU in 
our laboratory. However, there is no decrease in cellular or humoral immune 
responses . 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT \UMBES 

ZOl EY 00221-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30. 1987 



TITLE OF PROJECT ISO cnmrmcnrj or mas Titm must tn on on» mrm Mrwtn m» Ooroan.) 

Intraocula r Class II Antigen E xpression In Endotoxin-TnHnrPH Th.P■,•^^c 



PRINCIPAL INVESTIGATOR (Lai om»r profstnnat (mnonrmi t»>ow r>» Pnncio*' Invtsiigno/ ) (Ntmt. mw itDormmry. ana nsmam anmaaon) 



PI: Alan G. Palestine M.D. 



Others: Myung Kim M.D. 

Consuelo Muellenberg-Coulombre 
Robert B. Nussenblatt M.D. 



Head, Section on 

Clinical Immunology 

Visiting Fellow 

Chemist 

Clinical Director 



LI, NEI 



LI, NEI 

LI, NEI 

NEI 



COOPERATING UNITS (e mny) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Clinical Immunology 



INSTrrUTE AND LOCATION 

NEI, NIH, Bethesda. Maryland 



20892 



TOTAL MAN. YEARS: 
0.51 



PROFESSIONAL; 

0.^1 



OTHER: 



0.1 



CHECK APPROPRIATE BOXfES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues CB (c) Neither 



SUMMARY OF WORK (Us* ttmnotm unmajota type Do nor »xc»»e the spmot promote.) 

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. 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 inflammatory 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 
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. The findings were compared with the 
expression of class II antigen in passive and active intraocular Arthus. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES ■ PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT .MUMBES 



ZOl EY 00222-02 LI 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE Of PROJECT (80 cfmcmrz or mss Titta muit tn on one Une DmTwtn tnt tnfMn.) 

Immunopath ology In t he Eyes with Experimental Autoimmune Uveitis (EAU) 



PRINCIPAL INVESTIGATOR (Lnt otrmr pmlaxsmnti penonnti Otiow the Pnnapal Invstigttof ) (Ntmt, crx. iu>or9tory. tnO msmun HhhatKyi) 



PI: Chi-Chao Chan M.D. 

Others: Robert B. Nussenblatt M.D. 

Igal Gery Ph.D. 

Rachel R. Caspi Ph.D. 

Barbara Detrick Ph.D. 



Senior Staff Fellow LI, NEI 

Clinical Director NEI 

Head, Section on Experimental LI, NEI 

Immunology 
Visiting Associate LI, NEI 

Expert LI, NEI 



COOPERATING UNITS (H tny) 

University of Tokyo, School of Medicine (Manabu Mochizuki, M.D.) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN-YEARS: 
0.43 



PROFESSIONAL: 

0.43 



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 (Un tttnOtrtS unrwOuc^a Typt Do not (xcesO me tpac* proviata.) 

Identity and topographic localization of immunocompetent cells and alteration of 
surface marker on ocular resident cells in rodents with experimental autoimmune 
uveoretinitis by active immunization or adoptive transfer 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. 
Expression of major histocompatibility complex class II antigens on ocular 
resident cells such as RPE, retinal endothelium, keratocytes, fibroblast and 
ciliary epithelium was observed in different models of EAU. This antigen 
expression may play a certain role in the pathogenesis of EAU. Both 
infiltrating and alteration of class II antigens cell subpopulation can be 
modulated by cyclosporine and dexamethofeone treatment. 



""" '"-""'- '■'" 



CO t<«-*li 



DEPARTMENT Of HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PnCuECT MUMBES 



ZOl EY 00224-02 LI 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 

TITLE Of PROJECT (80 cAaracnrt or mu Tnm must tn on ont imt omrw9»n tne bon»n.) 

Sympathetic Ophthalmia: Immunopathological Findings 



J 



PRINCIPAL INVESTIGATOR (Usi Offw prottujonai (»nonn»i Dlo» in* Pnnae*' invtsiigMtor ) (ffm*. eot. wocyarory. una nsmuf afhuaoofi) 



PI: Chi-Chao Chan M.D. 

Others: Robert B. Nussenblatt M.D. 

Alan G. Palestine M.D. 

Toichiro Kuwabara M.D. 



Senior Staff Fellow LI, NEI 

Clinical Director NET 

Head, Section on Clinical LI, NEI 

Immunology 

Head, Laboratory of LOP, NEI 

Ophthalmic Pathology 



COOPERATING UNfTS (H tny) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
0.12 



PROFESSIONAL; 



0.12 



OTHER: 



CHECK APPROPRIATE BOX/ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



12 (b) Human tissues D (c) Neither 



SUMMARY Of WORK (Um stanoaro unfouotc lypa Do not cxcaae me ipac* provoue.) 

Iiranunocompetent cells and ocular resident cells in the ocular tissues from 
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 B lymphocytes 
were present in each case. A varied spectrum of immunopathological and 
histopathological findings may occur in clinically diagnosed sympathetic 
ophthalmia. The immunopathology resembles EAU induced by retinal soluble model. 
Exposure of uveal tissue outside the eye and adjuvant effect may be important in 
the pathogenesis of this disease in humans. 



PMC Cfv.^ ,C... ,,a^, 



QWO • 1 «*«1 I 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT MUMBES 

ZOl EY 00225-02 LI 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TfTLE OF PROJECT ($0 cnrtcnrz or mu Titm must tn on ont unt 0»tw»»n trm txxomn.) 

Post-Inflammatory Complications in Uveitis 



PRINCIPAL INVESTIGATOR ILat otrmr proitisjona: panonml Dtow m» Prmcifitl Inrtstigaior / (Ntmt ont mnratofy ana ruouM Itunoon) 

PI: Chi-Chao Chan M.D. Senior Staff Fellow LI, NEI 



Others: Robert B. Nussenblatt M.D, 
Richard P. Wetzig M.D, 
Francois Roberge M.D. 



Clinical Director 
Senior Staff Fellow 
Visiting Associate 



NEI 

LI, NEI 
LI, NEI 



COOPERATING UNITS (K any) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 
Section on Immunoregulation 



INSTTTUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN- YEARS: 
0,16 



PROFESSIONAL; 

0.16 



OTHER 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



W (b) Human tissues D (c) Neither 



SUMMARY Of WORK (Un stanoaro unnojcma typa. Do not axoaaa the Mpaca protnaae.) 

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. 



PMCKA^n.C... ,,»-, 



C»0 91 «.«1l 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



; PROJECT .NUMBER 

ZOl EY 00226-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 cheracfrs or leu Title must ht on one lint between tf>e bortiers.) 

Immunopathology of Ocular Onchocerciasis and Otner Parasitic Diseases 



PRINCIPAL INVESTIGATOR (Ust other prolessionH personnel below the Pnncipaf Investigator ) (Name^ title itbp'-iiory and msmutt emimboni 

PI: Chi-Chao Chan M.D. Senior Staff Fellow ' LI, NEI 



Others: 



Robert B. Nussenblatt M.D. 



Clinical Director 



NEI 



COOPERATING UNITS (It any) 

National Institute of Allergy and Infectious Diseases, Clinical Parasitic 
Diseases Section (Eric A. Ottesen, M.D.); World Health Organization (K. Awadzi, 
M.D.) 



LAB/BRANCH 

Laboratory of Iinmunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, MD 20892 



TOTAL MAN-YEARS 
0.3 



PROFESSIONAL; 

0.3 



OTHER: 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



IE] (b) Human tissues D (c) Neither 



SUMMARY Of WORK (Use standard unreduced type Do not exceed tf>e space prxxnOed.) 

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. Using the indirect immunoperoxidase 
method, autoimmune antibodies against outer segments of photoreceptors and inner 
neural layers of retina were identified in sera and ocular fluids from patients 
with onchocerciasis. These antibodies could not be absorbed by S-Ag nor IRBP. 
They may play a role in the retinal degeneration in onchocerciasis. 



PHRBtWl.a... 1/<U> 



e^o ti4.*i* 



DEPARTMENT Of HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBES 

ZOl EY 00227-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TPTLt OF PROJECT (BO cnarmcnrt or au litm must ht on on» unt otrwptn m* Oorort.) 

Histopathology of Pars Planitis and Experimental Autoimmune Uveitis 



PRINCIPAL INVESTIGATOR (Lat om»r proltsannt' prtonrmi owow tn» PnnaDti ininstigtmr / (Stmt, on* lunrmmry, tne rusoM ftmaoon) 

PI: Richard P. Wetzig M.D. Senior Staff Fellow LI, NEI 



Others: Robert B. Nussenblatt M.D. 

Chi-Chao Chan M.D. 

Barbara Detrick Ph.D. 

John J. Hooks Ph.D. 



Clinical Director NEI 

Senior Staff Fellow LI, NEI 

Expert LI, NEI 

Head, Section on Immunology LI, NEI 
and Virology 



COOPERATING UNITS (* any) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 
Section on Immunoregulation 



INSTTTUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS; 
0.58 



PROFESSIONAL: 

0.58 



OTHER 



CHECK APPROPRIATE BOX/ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



El (b) Human tissues O (c) Neither 



SUMMARY OF WORK (Un tmnOfC unrwauotO typt Do not •zcmO me spao* prwiaae.) 

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. 



-B^r »^-" "=— •-- 



G^O •!««•*• 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 

PERIOD COVERED 
October 1, 1986 to September 30, 1987 

TITLE OF PROJECT (80 cnamcnn or au Tiim must tn on ont »ni oantvvn me t/orouri.) 

Study of Ocular Glial Cells Involvement in Uveitis 



PROJECT MUM6ES 

ZOl EY 00228-02 LI 



PRINCIPAL INVESTIGATOR (LSI o(rw pixMtujonti penonn»i c»tow m* Pnnupai In^^siigttor ) Ifitm*. dm. moontoiy. mna msfflut* affiMOon; 

PI: Francois Roberge M.D. Visiting Associate LI, NEI 



Others: Robert B. Nussenblatt M.D. 
Rachel Caspi Ph.D. 



Clinical Director 
Visiting Associate 



NEI 
LI, NEI 



COOPERATING UNITS (H mny) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 
Section on Immunoregulation 



INSTrrUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN- YEARS: 
0.92 



PROFESSIONAL: 
0.92 



OTHER- 



CHECK APPROPRIATE BOXTES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues El (c) Neither 



SUMMARY OF WORK (Uu lanomw unmauc»a typt. Do not azcaec in« tpaca promome.) 

The work extended our ongoing study of interactions between the retinal glial 
Miiller cell and T lymphocytes. In an in vitro co-culture system, Miiller cells 
had been shown to exert a profound inhibitory influence on antigen and IL-2 
driven proliferation of T helper cell lines. Investigations of the nature of 
the inhibitory moiety revealed that it was sensitive to proteinase. In further 
studies, we demonstrated that Miiller cells can produce interleukin 1 (IL-1) 
activity and that in conditions where their inhibitory action is removed they 
display the capacity to efficiently function as antigen presenting cells. 



PMS 60*0 (Rev 1/64) 



CVO (K.*!* 



DEPARTMENT Of HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUM6ES 

ZOl EY 00229-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE O^ PROJECT (80 cnamcmrt or m*s Titm mutt tit on on* ime Omrwen tn» Oorvn.) 

Assessment of the Size of the Leak Induced in Retinal Vessels Using PITC-Dextrans 



PRINCIPAL INVESTIGATOR (Lat otrmr pmttgtnnai ptrvxmai ouow tn» fnncffi mvtttiftof ) (Hmm* OM ttaorutorf. una rumui* tflmaooni 

PI: Alan G. Palestine M.D, Head, Section on Clinical 

Immunology 



LI, NEI 



Others: Susan Lightman 



M.D. 



Visiting Fellow 



LI, NEI 



COOPERATING UNITS (H any) 

Laboratory of Ophthalmic Pathology, National Eye Institute (Toichiro Kuwabara); 
Laboratory of Ophthalmic Pathology, National Eye Institute (Laura Caspers-Velu) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Clinical Immunoloev 



INSTITUTE AND LOCATION 

NEI. NIH, Bethesda. Maryland 20892 



TOTAL MAN- YEARS: 

0.3 



PROFESSIONAL: 

0.3 



OTHER; 



CHECK APPROPRIATE BOX(ES) 

O (a) Human subjects 
D (a1) Minors 
D (a2) interviews 



D (b) Human tissues IB (c) Neither 



SUMMARY Of WORK (Un ttmnow unrwouota typt Do not axCMO me xptca pro<nota.j 

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 
sodixOTi fluorescein in the inflamed retina. The sites of large molecule leakage 
show ultrastructural evidence of open tight junctions whereas the areas that 
leak only sodium fluorescein have closed tight junctions. 



PMS 60*0 (hey 1/M) 



C^O tl ««•!• 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



ZOl EY 00230-02 LI 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE Of PROJECT (BO cnracnn or mu Titm must In on on* ant D»rw^n tr» borota.) 

Quantitative Assessment of Retinal Vascular Permeability 



PRINCIPAL INVESTIGATOR (Lat om»' profuxinai pertonmi bnow (n» Pnnaoai lny»siig*tof ) fStmt. oo» mDofmmty. ana ri*mut» arhMDon; 

PI: Alan G. Palestine M.D. Head, Section on Clinical LI, NEI 

Immunology 



Others: 



Stephanie Skolik 



M.D. 



Research Fellow 



LI, NEI 



COOPERATING UNPTS ('' anyj Laboratory of Neurosciences, National Institute on Aging (Emanuel 
Rechthand, M.D.); Laboratory of Neurosciences, National Institute on Aging (Stanley 
Rapoport, M.D.); Laboratory of Mechanisms of Ocular Diseases, Section on Molecular 
Pharmacology (Peter Kador, Ph.D.) 



LAB3 RANCH 

Laboratory of Immunology 



SECTION 

Section on Clinical Immunology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
0.33 



PROFESSIONAL: 



0.33 



OTHER. 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues El (c) Neither 



Summary Of work (Utt tmnovo unnaucma typt Oo not »xc9»a tne xpac* promoaa.) 

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. 
Increased leakage was observed in clinically and acutely hypertensive rats. 
Increased leakage was also observed in galactosemia rats. This leakage was 
reversed by treatment with an aldose reductase inhibitor. 



PHS 6040 (R«v 1/641 



C^C ti «-*l* 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



ZOl EY 00231-02 LI 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE O^ PROJECT (BO cffmcnri or mu Tni» must tr on one tnt Miw»n trm 

Cell Surface Antigens on Retinoblastoma Cells 



PRINCIPAL INVESTIGATOR ^Lir otrm' pnjfstnnti perMonrm: 0»K>w tn* Fniapt' inr»stigttor ) (Ntmt, ont moorttory tna rtinum trtmtoonj 

PI: 



Barbara Detrick 

Others: John J. Hooks 

Gerald J. Chader 
Merlyn Rodrigues 

Caroline Percopo 



Ph.D. 


Ph.D. 


Ph.D. 


M.D., 



Expert 



LI, NEI 



Ph.D. 



A.B. 



Head, Section on Immunology LI, NEI 

and Virology 
Chief LVR, NEI 

Head, Section on Clinical LOP, NEI 

Eye Pathology 
Biologist LI. NEI 



COOPERATING UNITS ^/r .ny; Walter Reed Army Medical Center, Washington, D.C. (Magda 
Tomaszewski, M.D.); Walter Reed Army Medical Center, Washington, D.C. (David Katz, 
M.D.); Duke University, Durham, North Carolina (Barton Haynes, M.D.); Ruprecht- 
Karl's U niversity. Heidelberg, CerTnany fFllen Kraiis-Markiw , K.D.) 



LAB/BRANCH 

Laborato ry nf TniTTinnnl 



iigX. 



SECTION 

Section on Immunoregulation 



INSTTTLTrE AND LOCATION 



NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
0.65 



PROFESSIONAL: 

0.A5 



OTHER. 



0.2 



CHECK APPROPRIATE BOX/ES) 

El (a) Human subjects 
D (a1} Minors 
D {a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Uu ttanowv imnauota rype. Oo nor •ZCM0 the tpaca pnxnote.) 

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 identified the presence of HLA-DR and HLA-DQ antigens on a 
population of undifferentiated malignant cells of the retina. This study 
provides the initial description of these 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, additional investigations are in progress. One 
approach focuses on the possible role of class II antigens in cellular 
differentiation or immune reactivity. A second examines 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. Finally, a third study will examine the role of IFN-gamma as a 
differentiating agent of this tumor. 



C»0 1 1 «.•!• 



y'l-yr^fiw 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT JMUMBES 



ZOl EY 00232-02 LI 



PERIOD COVERED 

October 1, 1986 to September 30. 1987 

TfTLE OF PROJECT (BO cft«r»cr»n or mts Tiut must Irt on one lint o»tw—n tne ooramri.) 

Interferon System in Cellular Function and m^P^^f^ 



PRINCIPAL INVESTIGATOR (Lat om»' pmtmuionti parionn»l tmow m* fnncieai Inmtigtmr I (Namt, m» lumeatoiy. ana ntoiutc aftmaoon) 



PI: John J, Hooks Ph.D. 



Others: Barbara Detrick Ph.D. 

Caroline Percopo A.B. 

Christian Hamel M.D. 

Muriel Kaiser-Kupfer M.D. 



Head, Section on Immunology LI, NEI 
and Virology 

Expert LI, NEI 

Biologist LI, NEI 

Visiting Fellow LI, NEI 

Head, Section on Ophthalmic CB, NEI 



COOPERATING UNITS (H any) 

Newjork University, School of Medicine, Department of Microbiology (Jan Vilcek, 



LAB«RANCH 

Laboratory of Immunology 



SECTION 

Section on Immunology and Virology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda. Maryland 20892 



TOTAL MAN- YEARS; 

1.15 



PROfESSIONAL; 
0.75 



OTHER. 



0.4 



CHECK APPROPRIATE BOX/ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues IS (c) Neither 



SUMMARY OF WORK (Uta sxanoara unrtauctO typa. Do not axc^aO the spaca promoaO.) 

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 . 



PHS 6040 Ihev 1/M) 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT .\UMB£= 

ZOl EY 00233-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE Of PROJECT f$0 cnmrmawri or ou Tnm must tn on orm knt Omrw—n tn» Domn.) 

Studies on the Bioregulatory Aspects of the Retinal Pigment Epithelial Cell 

PRINCIPAL INVESTIGATOR (Lat otrmr profujonn persormn osfow tnm Pnnupti Intrmittgttor.) ISamt. OM. moortmry. ana ntmun arNwiw); 



PI: John J. Hooks Ph.D. 



Others: Barbara Detrick Ph.D. 

Caroline Percopo A.B. 

Susan Robbins Ph.D. 

Laura Caspers-Velu M.D. 



Head, Section on Immunology 
and Virology 

Expert 
Biologist 

Postdoctoral Fellow 
Visiting Associate 



LI, NEI 



LI, NEI 

LI, NEI 

LI, NEI 

LOP, NEI 



COOPERATING UNITS f/r«.w Hopital St. Louis, Paris, France (Lawrence Bowsell, M.D.); 
Institute Gustave Rowsse, Villjuif, France (Alain Bernard, M.D.); National 
Institute of Dental Research, Laboratory of Microbiology & Immunology (Reuben 
Siraganian, M.D.) 



LAB^ RANCH 

Laboratory of Immunology 



SECTION 

Section on Immunology and Virology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS; 
1.A5 



PROFESSIONAL 

1.25 



OTHER: 



0.2 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) lnterviev« 



13 (b) Human tissues D (c) Neither 



SUMMARY Of WORK (U$t ttanavc unrtoucmo typt Do not tieaee tne tpaca promote.) 

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 human 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. 



-^ 



C I^Ott *•• » • 



DEPARTMENT OF HEALTH AND HUMAN SERVICE: • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT MuMBcS 



ZOl EY 0023A-02 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE OP PROJECT (BO cnarucmn or •» Tm, mior tn on on* imt Dmtw—n trw ooroan.) 

MHC Class II Antigens in the Pathogenesis of Inflammatory Diseases 



PRINCIPAL INVESTIGATOR (Lat omur profunnti parxonnti o»io» an frmcipai Inrtsiigttor ) (Namt, on*, moorwtory. mna mmun aftikaoon) 



PI: John J. Hooks Ph.D. 



Others: Barbara Detrick Ph.D. 

Christian Hamel M.D. 

Chi-Chao Chan M.D. 

Robert B. Nussenblatt M.D. 



Head, Section on Immunology 
and Virology 

Expert 

Visiting Fellow 
Senior Staff Fellow 
Clinical Director 



LI, NEI 



LI, NEI 

LI, NEI 

LI, NEI 

NEI 



COOPERATING UNITS (K 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; 
0.65 



PROFESSIONAL: 

0.65 



OTHER 



CHECK APPROPRIATE BOXfES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues El (c) Neither 



SUMMARY OF WORK (Uf gnnaarxi unraoooae typt Do not mxcte the uxca (nxnoaa.) 

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. Treatment with monoclonal anti-la antibodies 
diminished the clinical disease and the expression of MHC class II antigens. 
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. Moreover, we evaluated the effect of cyclosporin A 
on the immunopathological lesions in Sjogren's syndrome. We found that 
cyclosporin treatment resulted in a decrease in both T cell infiltration and a 
decrease in HLA-DR antigen expression. 

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 6040 (fiev 1/S41 



C*0 (I*.*!! 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 

PERIOD COVERED 
October 1, 1986 to September 30, 1987 



pROjEC' number 
ZOl EY 00235-02 LI 



TfTLE OF PROJECT (SO eft»f»ci»n or mi Tom musi tn or. on» un* t»iw»»n trw ooroft.) 

Identification and Modulation of Class II Antigens 



PRINCIPAL INVESTIGATOR (Lat omtr proltuionMi personrmi osotr m* PnnoDai Invwitigttoi I INtmt, tan mooratory. »na ratnim aftmaoon/ 

PI: Barbara Detrick Ph.D. Expert LI, NEI 



Others: John J. Hooks 



Richard Wetzig 
Chi-Chao Chan 
Caroline Percopo 
Robert B. Nussenblatt 



Ph.D. Head, Section on Immunology LI, NEI 

and Virology 

M.D. Senior Staff Fellow LI, NEI 

M.D. Senior Staff Fellow LI, NEI 

A.B. Biologist LI, NEI 

M.D.. Clinical Director NEI 



COOPERATING UNITS fA.ny; g^^ ^^^ ^^^ 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, 
N.D.) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN- YEARS: 
0.A3 



PROFESSIONAL; 

0.33 



OTHER. 



iLJ- 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
O (a1) Minors 
□ (a2) Interviews 



D (b) Human tissues CB (c) Neither 



SUMMARY OF WORK (Utt ttmnatrv unntauc^O typt Do not cicmC tht tpac* provote.) 

Class II antigens are membrane bound glycoproteins encoded by genes in the mixed 
histocompatibility complex. Their expression is critical to immune reactivity. 
Although most immune cells constitutively express class II antigens, some non- 
immune cell types can be induced to demonstrate these molecules under selected 
conditions, such as an immunologic or degenerative event. Based on our earlier 
data, which demonstrated that retinitis pigmentosa patients had an alteration in 
IFN-gamma production and class II antigen expression and rpe cells can, in 
special instances, express class II antigens, we expanded our studies to 
evaluate class II antigen expression in a variety of ocular situations. 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 (sympa- 
thetic 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. 
Finally, we demonstrated that EAU could be altered with anti-la therapy. In 
this study EAU animals receiving monoclonal anti-la antibodies experience not 
only less ocular inflammation but also a delay in the onset of EAU. Moreover, 
immunocytochemistry analysis revealed that eyes from these animals expressed 
less la antigen as well as a diminution of infiltrating macrophages and 
lymphocytes. These data show that anti-la treatment significantly modifies the 
course of EAU in the rat. We are continuing to investigate the effects of other 
potent modulators such as IFN-gamma 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. 



c^^^^«j«ii 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



, PROJECT NUMBER 



Z01 EY 00237-02 LMOD 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (80 chtrtcttrs or toss TlOa must ht on ona lint butw—n tht borOtn.) 

Characterization of the Primate Lens 



PRINCIPAL INVESTIGATOR (List other prottssionai personnel below the Pnnapel Investigator ) (Name, title, laboratory, and msotute afhliaoon) 

PI: Paul Russell Ph.D. Research Chemist LMOD, NEI 
Others: Masao Nakamura M.D. Visiting Associate LMOD, NEI 



COOPERATING UNITS (» any) 

Division of Cancer Research, University of Toronto (S. 
L.-C. Tsui) 



Meakin, M. Breitman, 



LAB/BRANCH 

Laboratory of Mechanisms of Ocular Diseases 



SECTION 

Section on Cataract 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS; 



1.7 



PROFESSIONAL; 



1.7 



OTHER: 



0.0 



CHECK APPROPRIATE BOX(ES) 

n (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



[^ (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Use standard unreduced type Do not enceed the apace provided.) 

The most prevalent proteins in the human lens are the crystallins. One of the 
major groups of these proteins are called gamma crystallins. Because of altera- 
tions in these crystallins upon aging in the lens and the difficulty in getting 
purified polypeptide, the protein sequences of these crystallins are not known. 
The nucleotide sequences of the "T-crystallin family are known, however. As an 
alternate approach for assigning these genes to specific polypeptides, the genes 
for three of the Y-crystallins were stably integrated into mouse L-cells, a 
fibroblast cell line. The products of these genes that were expressed in the 
fibroblasts could then be compared to the proteins found in the human lens. 
Three of the human gamma crystallins expressed in the mouse cells have been shown 
to have properties identical to the Y-crystallins found in the human lens. 

The aging of crystallins in vivo has been difficult to study because che exact 
mechanism for the alterations is not known. By using the Y-crystallins expressed 
in vitro in a mixed-function oxidation system, the microheterogeneity and shift 
to more acidic crystallin components found in the aging lens has been duplicated 
in vitro. 

In addition to the work on the Y-crystallins, studies with lens membrane have 
also been done. A major protein in the membrane fraction of cell lenses has been 
identified as calpactin I. This protein is known to associate with actin in the 
presence of calcium and phospholipid. This protein may play a major role in the 
process of differentiation of lens epithelium to lens fiber. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



PROJECT NUMBER 



Z01 EY 00238-02 LMDB 



TITLE OF PROJECT (80 characters or less Title rrjust fit on one line between the borders ) 

Proto-oncogene Expression During Lens Differentiation and Development 



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator ) (Name, title, laboratory, and institute affiliation) 

PI: Peggy Zelenka Ph.D. Geneticist LMDB, NEI 



Others: Luke Pallansch 
Howard Beswick 



Ph.D. Staff Fellow 
Ph.D. Visiting Fellow 



LMDB, NEI 
LMDB, NEI 



COOPERATING UNITS (if any) 

liana Keshet 



Ph.D. 



Visiting Fellow 



LMDB, NEI 



LAB/BRANCH 

Laboratory of Molecular and Developmental Biology 



SECTION 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS 



2.3 



PROFESSIONAL: 



2.0 



OTHER; 



0.3 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues H (c) Neither 



SUMMARY OF WORK (Use standard unreduced Type Do not exceed the space provided.) 



This project investigates the expression of proto-oncogenes 
differentiation of embryonic lens epithelial cells to form 1 
seeks to determine the specific function of the correspondin 
the developing lens. Using radioactively labeled DNA probes 
demonstrated that levels of c-myc mRNA are transiently eleva 
few hours after the initiation of differentiation in vitro, 
c-myc mRNA seems to be post-transcriptionally regulated, as 
small-scale nuclear run-on transcription assay developed in 
which allows measurements to be made on as few as 10° cells, 
lipoxygenase pathway of arachidonic acid metabolism produce 
of c-myc mRNA, which also seems to be post-transcriptionally 
Analysis of the arachidonic acid metabolites synthesized by 
epithelial explants has confirmed that elevated c-myc mRNA 1 
with the disappearance of a specific lipoxygenase pathway me 



during the 

ens fiber cells, and 

g gene products in 

we have 
ted during the first 

The elevation of 
determined by a 
this laboratory. 

Inhibitors of the 
a similar elevation 

regulated. 
differentiating lens 
evels are correlated 
tabolite. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PBOjECT MUM6ES 



ZOl EY 00239-01 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE Of PROJECT (90 cnarmcnn or wu T(K» mtat tn on ont mh 0mrw9»n irm Domn.) 

Penetrating Keratoplasty in the Rat 

PRINCIPAL INVESTIGATOR (Lai otnmr profttionti p»nonn»i t»iow mm Pnnapai mvwtiigator ) (N»m», oi». mooftoiy. mna msmut* anmaoon) 

PI: Edward J. Holland M.D. Senior Staff Fellow 



Others: Chi-Chao Chan M.D. 

Richard P. Wetzig M.D. 
Robert B. Nussenblatt M.D. 



Senior Staff Fellow 
Senior Staff Fellow 
Clinical Director 



LI, NEI 

LI, NEI 
LI, NEI 

NEI 



COOPERATING UNITS (K any) 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on Immunoregulation 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN-YEARS: 

0.38 



PROFESSIONAL; 

0.38 



OTHER 



CHECK APPROPRIATE BOX^) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



O (b) Human tissues H (c) Neither 



SUMMARY OF WORK (U*t txmnotrV unr90ix»e ryt». Do not azcMcr me toac* piwate.) 

A rat penetrating keratoplasty model was developed to evaluate the corneal 
allograft rejection reaction. Using Brown Norway rats as donor for Lewis rats 
and by not removing sutures, a rejection rate of approximately 90% could be seen 
by the third week. Inflammation of the grafts could be seen in the second week 
followed by vascularization. Monoclonal antibodies to T-lymphocyte subsets and 
major histocompatibility complex (MHC) antigenic markers in the rat are now 
available which allow for the delineation of the acute corneal rejection 
reaction. 



C^O •! ««*1* 



OEPARTVENT OT HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 

NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT MUM6ES 

ZOl EY 00240-01 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE Of PROJECT (BO cnmrmctmn or mu Torn musi tn on ont ut* MrtvMn m* oofomn.) 

Virus Infections in the Eye 



PRINCIPAL INVESTIGATOR (La: otntr prvtatannti pertonnti o»<o« tnt Prwtaotl Invmsiigator ) (Ntmt. om. laooftory. ana mgmut* anmmaon) 

PI: John J. Hooks Ph.D. Head, Section on Immunology 

and Virology 



LI, NEI 



Others: 



Susan Robbins Ph.D. 
Christian Hamel M.D. 
Barbara Detrick Ph.D. 
Caroline Percopo A.B. 
Robert B. Nussenblatt M.D. 



Postdoctoral Fellow 
Visiting Fellow 
Expert 
Biologist 
Clinical Director 



LI, NEI 
LI, NEI 
LI, NEI 
LI, NEI 
NEI 



COOPERATING UNITS (' any) 

See attached 



LAB/BRANCH 

Laboratory of Immunology 



SECTION 

Section on iTmnunology and Virology 



INSTTTUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS. 
0.96 



PROPESSIONAL. 

0.86 



OTHER; 



0.1 



CHECK APPROPRIATE BOX(ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Um sttnova unnaucto typt. Do nor •ic—e tnt socc* pnxnoaa.) 

During the past year we have initiated studies to evaluate the various virologic 
and iiranunopathologic processes which occur when viruses replicate in the ocular 
microenvironment . This is a new project which is presently composed of three 
areas. (1) Evaluation of virus spread in HSV-1 induced retinitis. (2) Studies 
on coronavirus infection in ocular and optic nerve cells. (3) Possible role of 
viruses in human eye diseases. 

Retinitis following anterior chamber inoculation of herpes simplex virus (HSV-1) 
is an interesting model of viral spread and virus induced disease. During the 
past year we have elucidated some of the pathologic mechanisms involved in this 
disease. We found that footprints of the immune system (IFN-gamma and MHC class 
II antigen expression) can be identified in the protected retina strongly 
indicating that it is the immune system which protects the retina from virus 
destruction. Moreover, we identified the virus in the ciliary body and ciliary 
nerves suggesting that this may be the mode of spread of the virus to the 
uninjected eye. Elucidation of virus spread and activation in the retina may 
provide insight into these same mechanisms in human disease, such as ARN. 

We have initiated studies to evaluate coronarvirus infections in the eye and 
optic nerve. Preliminary studies using monoclonal anti-virus receptor antibody 
has identified selected cells within the eye which express virus receptors. 
These studies will be extended to evaluate virus induced ocular damage. 



C^O •< *«*t> 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PBOjECT NUM6ES 

ZOl EY 00241-01 LI 



PERIOD COVERED 
October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO cffrtcnrs or »ts. T?o» must tn 0.1 oo» imt Omtw—n mt ooromrz.) 

Iramunopathology of Ocular Diseases 



PRINCIPAL INVESTIGATOR (List otnur pmrtutonai p»rjonn»/ omjmt m* PnnaaH Invtsiigttor 1 (Nam», m». laoorttOfY. ana msmjt* tiruiaoai) 

PI: Chi-Chao Chan M,D. Senior Staff Fellow LI, NEI 



Others: Robert B. Nussenblatt M.D. 
Alan G. Palestine M.D. 

Edward J. Holland M.D. 



Clinical Director NEI 

Head, Section on Clinical LI, NEI 

Immunology 

Senior Staff Fellow LI, NEI 



COOPERATING UNITS ((f «nw Zhongshan Ophthalmic Center, Guangzhon, China (Winifred Mao, 
M.D.); University of Iowa (Jay H. Krachmer, M.D.); Georgetown University Center 
for Sight (Michael Lemp, M.D. and Garth Stevens, Jr., M.D.) 



LAB/a RANCH 

Laboratory of Immunology 



SECTION 
Section on Immunoregulation 



INSTrruTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN- YEARS: 
1.52 



PROFESSIONAL; 

1.52 



OTHER; 



CHECK APPROPRIATE BOX<ES) 

D (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



E] (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Uf stunova unnoucta fyp». Do net axoaeO ffw spaca provKma.) 

Ocular specimens from human ocular tissues with various diseases, such as 
uveitis, conjunctival and corneal diseases, and ocular metabolic genetic 
diseases were studied using immunoperoxidase technique as well as light and 
electron microscopic evaluation. In uveitis, immunocompetent cells and 
lymphokines are critical in the reflection of clinical diagnosis, course and 
prognosis. In non-uveitis, alteration of cellular membrane surface markers and 
intracytoskeleton on the ocular resident cells may imply damages and 
abnormalities in these diseases. 



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PERIOD COVERED 

October 1, 1986, to September 30, 1987 



PROJECT NUMBER 



ZOl EY 00242-01 LSR 



TITLE OF PROJECT (80 characters or /ess Title must fit on one line between ttie borders.) 

Visual Motor Control of Saccadic Eye Movements 



PRINCIPAL INVESTIGATOR (Ust other professional personnel below the Principal Investigator ) (Name, title, laboratory, and institute affiliation) 



PI: Robert H. Wurtz Ph.D. 

Others: Lance M. Optican Ph.D. 

David M. Waitzman M.D. , Ph.D. 

Terence Paul Ma Ph.D. 



Chief LSR, NEI 

Res. Biomed. Engineer LSR, NEI 

Staff Fellow LSR, NEI 

Guest Researcher LSR, NEI 



COOPERATING UNITS (H any) 



LAB/BRANCH 

Laboratory of Sensorimotor Research 



SECTION 

Visuomotor Integration Section 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 



20892 



TOTAL MAN-YEARS: 

2.1 



PROFESSIONAL 

1.3 



OTHER 



0.8 



CHECK APPROPRIATE BOX(ES) 

n (a) Human subjects 
D (a1) Minors 
D (a2) Interviews 



D (b) Human tissues K (c) Neither 



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the space provided.) 

We recorded single cell activity in the superior colliculus of monkeys trained to 
make rapid or saccadic eye movements. As reported previously, some cells 
discharged in relation to saccades made to targets in one area of the visual 
field, others with only saccadic eye movement made to a given part of the visual 
field. In addition, other cells have been identified that discharge only before 
saccades made to the location of a remembered target. Detailed information on 
the relation of cell discharge and the metrics of the saccade were collected for 
use in refining a neural model of the saccadic system. 



PHS 6O40 (Rev 1/84) 



OPO •14-CII 



DEPARTMENT OF HEALTH AND HUMAN SERVICES • PUBLIC HEALTH SERVICE 
NOTICE OF INTRAMURAL RESEARCH PROJECT 



PROJECT NUMBER 



Z01 EY 00243-01 LMOD 



PERIOD COVERED 

October 1, 1986 to September 30, 1987 



TITLE OF PROJECT (BO chartctars or lais Trt/e must M on ont Una betwean tfia bontert.) 

Ocular Cells Cultured under Normal Diabetic Conditions 



PRINCIPAL INVESTIGATOR (Ust otttar prolaiiional parsonnal below tha Pnnapal Invastigator) (Nama. ma. laboratory, and insmuta athliaoort) 



PI: Bruce A. Pfeffer Ph.D. 



Others: W. Gerald Robison, Jr. Ph.D. 



Senior Staff 
Fellow 



LMOD, NEI 



Chief, Section LMOD, NEI 
on Pathophysiology 



COOPERATING UNITS (» mfy) 



LAB/BRANCH 

Laboratory of Mechanisms of Ocular Diseases 



SECTION 

Section on Pathophysiology 



INSTITUTE AND LOCATION 

NEI, NIH, Bethesda, Maryland 20892 



TOTAL MAN-YEARS: 



1.0 



PROFESSIONAL: 



2.0 



OTHER: 



CHECK APPROPRIATE BOX<ES) 

D (a) Human subjects 
D (al) Minors 
D (a2) Interviews 



El (b) Human tissues D (c) Neither 



SUMMARY OF WORK (Usa standard unraducad typa Do nor axcaed tha tpaca pfOviOad.) 

Evidence exists that the retinal pigment epithelium (RPE) is one of the affected 
tissues in diabetic ocular disease. Specifically, the integrity of the blood- 
retinal barrier at the level of the RPE may be compromised. We are utilizing 
cultured human retinal pigment epithelium as a potential in vitro model system to 
study the effects of elevated hexose on these cells. RPE incubated with medium 
containing 30 mM galactose accumulates sugar alcohol (polyol) and loses myo- inosi' 
tol , and these effects are reversed when an aldose reductase inhibitor is present 
in the high galactose medium. This suggests that aldose reductase may be active ir 
RPE and that the polyol accumulation may contribute to impairment of RPE function 
in diabetes. The deficit does not appear to be at the level of the sodium, 
potassium-ATPase. 



bH 






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