Loss of Vision - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

LOSS OF VISION A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Loss of Vision: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00675-8 1. Loss of Vision-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on loss of vision. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON LOSS OF VISION......................................................................................... 3 Overview........................................................................................................................................ 3 Federally Funded Research on Loss of Vision ................................................................................ 3 The National Library of Medicine: PubMed ................................................................................ 23 CHAPTER 2. NUTRITION AND LOSS OF VISION ............................................................................... 37 Overview...................................................................................................................................... 37 Finding Nutrition Studies on Loss of Vision............................................................................... 37 Federal Resources on Nutrition ................................................................................................... 38 Additional Web Resources ........................................................................................................... 38 CHAPTER 3. ALTERNATIVE MEDICINE AND LOSS OF VISION ........................................................ 41 Overview...................................................................................................................................... 41 National Center for Complementary and Alternative Medicine.................................................. 41 Additional Web Resources ........................................................................................................... 42 General References ....................................................................................................................... 43 CHAPTER 4. BOOKS ON LOSS OF VISION ......................................................................................... 45 Overview...................................................................................................................................... 45 Book Summaries: Online Booksellers........................................................................................... 45 APPENDIX A. PHYSICIAN RESOURCES ............................................................................................ 49 Overview...................................................................................................................................... 49 NIH Guidelines............................................................................................................................ 49 NIH Databases............................................................................................................................. 51 Other Commercial Databases....................................................................................................... 53 APPENDIX B. PATIENT RESOURCES ................................................................................................. 55 Overview...................................................................................................................................... 55 Patient Guideline Sources............................................................................................................ 55 Finding Associations.................................................................................................................... 58 APPENDIX C. FINDING MEDICAL LIBRARIES .................................................................................. 61 Overview...................................................................................................................................... 61 Preparation................................................................................................................................... 61 Finding a Local Medical Library.................................................................................................. 61 Medical Libraries in the U.S. and Canada ................................................................................... 61 ONLINE GLOSSARIES.................................................................................................................. 67 Online Dictionary Directories ..................................................................................................... 67 LOSS OF VISION DICTIONARY ................................................................................................ 69 INDEX .............................................................................................................................................. 107

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with loss of vision is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about loss of vision, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to loss of vision, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on loss of vision. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to loss of vision, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on loss of vision. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON LOSS OF VISION Overview In this chapter, we will show you how to locate peer-reviewed references and studies on loss of vision.

Federally Funded Research on Loss of Vision The U.S. Government supports a variety of research studies relating to loss of vision. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to loss of vision. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore loss of vision. The following is typical of the type of information found when searching the CRISP database for loss of vision: •

Project Title: AGE RELATED MACULOPATHY-DRUSEN BIOGENESIS Principal Investigator & Institution: Anderson, Don H.; Director; Neuroscience Research Institute; University of California Santa Barbara 3227 Cheadle Hall Santa Barbara, Ca 93106 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 30-APR-2004

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Summary: (Verbatim from applicant's abstract): Age-related macular degeneration (AMD) is characterized by the progressive loss of vision in the central visual field attributable to atrophic, exudative and/or hemorrhagic changes in the macula. One of the hallmarks of AMD is the accumulation of extracellular deposits known as drusen between the retinal pigmented epithelium (RPE) and its blood supply, the choriocapillaris. In this project, our working hypothesis is that specific drusenassociated molecules accumulate in the cytoplasm, or along the basal surface, of "compromised" RPE cells in advance of actual drusen formation. One aim of the proposed research, therefore, is to characterize the role of the RPE in drusen biogenesis. Secondly, having confirmed that a number of drusen-associated molecules do, in fact, have local cellular sources in the retina, RPE, and/or choroid, we propose to determine whether any of these local cell types make a significant biosynthetic contribution to drusen. Accordingly, we propose to identify the relevant cell types, and to determine whether any of these drusen-associated molecules are expressed differentially in individuals with drusen or AMD. Differential expression of gene transcripts in target tissues [cells] in the retina, RPE, and choroid will be analyzed quantitatively using an automated fluorogenic detection system based upon the reverse transcriptasepolymerase chain reaction (RT-PCR). In pursuing these studies, we hope to determine whether changes in the expression of one or more of these genes contributes in a significant way to the cascade of degenerative changes that ultimately manifests itself as AMD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AGE-RELATED MACULAR DEGENERATION PREVENTION TRIAL Principal Investigator & Institution: Fine, Stuart L.; Professor & Chairman; Ophthalmology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 07-DEC-1998; Project End 30-NOV-2003 Summary: Age-related macular degeneration (AMD) is the leading cause of blindness among adults in the United States and several Western countries. Approximately 90% of the blindness is attributable to the neovascular form of AMD and the remainder is attributable to pigment epithelial detachment and geographic atrophy. The Macular Photocoagulation Study has shown that laser treatment is effective in reducing the extent of vision loss in eyes with neovascular AMD. However, most lesions are not amenable to laser treatment and even with treatment visual acuity deteriorates to an average of 20/250 to 20/320. There are no other proven treatments for the advance forms of AMD. Prevention of vision loss from the advanced forms of AMD would have profound public health implications. If an intervention were only 30% effective in preventing choroidal neovascularization (CNV) within the high-risk population, the rate of legal blindness from AMD could be cut in half. The presence of large drusen in the macula is a strong predictor of the development of CNV. Low intensity laser treatment causes high-risk drusen to disappear in most eyes. Controlled, pilot, clinical trials on the effect of laser treatment on development of CNV and loss of vision are underway on two groups of patients: patients with bilateral large drusen and patients with unilateral CNV and the second (fellow) eye with large drusen. Initial reports provide evidence of an increased rate of CNV in treatment fellow eyes, at lest for the first year after treatment. For eyes of patients with bilateral drusen, two small clinical trials show evidence of decreased CNV and better vision in treated eyes at 3 years and one large trial shows little difference between treated and untreated eyes through 18 months. The large segment of the population that might benefit, or be harmed, by laser treatment mandates a thorough evaluation of the treatment. We propose the Complications of

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Age-related Macular Degeneration Prevention Trial (CAPT) to assess the safety and effectiveness of laser treatment in preventing loss of vision among patients with bilateral drusen. Change in visual acuity will be the primary outcome variable. Secondary outcome measures will be the incidence of CNV, pigment epithelial detachment and geographic atrophy, change in contrast threshold, and change in critical point size for reading. In addition, the participating patients will be described with by their scores on both general and vision specific quality of life assessments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANTIGEN CHORIORETINOPATHIES

IDENTIFICATION

IN

OCCULT

Principal Investigator & Institution: Bennett, Jeffrey L.; Neurology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): Acute zonal occult outer retinopathy, multiple evanescent white dot syndrome, acute macular neuroretinopathy, acute idiopathic blind spot enlargement syndrome, multifocal choroiditis, punctuate inner choroidopathy, and diffuse subretinal fibrosis syndrome are a group of chorioretinal inflammatory disorders of unknown etiology. These disorders possess common clinical features, and affected individuals may evolve from one condition to another during their clinical course. Vision loss may vary from mild to severe. To date, however, there are no absolute criteria to define disease subtypes, no available markers to diagnose disease or gauge prognosis, and no effective therapies. As a result, debate remains as to whether these disorders represent a related spectrum of inflammatory chorioretinopathies. Pathologic specimens have revealed a B-cell predominant inflammatory infiltrate with antibody deposition providing a rationale for our hypothesis that antibodies play a role in the pathogenesis of these disorders and are directed against retinal or choroidal antigens that trigger or propagate disease. To identify an antigen specific to occult chorioretinopathies (OC) we will: (1) identify clones in a human uveal cDNA expression Library and a random peptide library whose products react with serum from OC patients; (2) determine the disease-specificity of candidate QC-specific antigens and peptides by screening sera from patients with QC and control ocular uveitides; and (3) characterize, using molecular biologic techniques, OC-specific clones and study their pattern of expression in the retina and choroid. Identification of OC-specific markers will help classify these occult inflammatory disorders as a specific nosologic entity, generate biologic markers to diagnose preclinical and clinical disease, and develop therapeutic strategies to prevent loss of vision in affected individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: APPLIED VISUAL PERFORMANCE TESTS Principal Investigator & Institution: Brabyn, John A.; Director/Senior Scientist; SmithKettlewell Eye Research Institute Research Institute San Francisco, Ca 94115 Timing: Fiscal Year 2002; Project Start 01-JUL-1993; Project End 31-JAN-2004 Summary: The US population is aging dramatically. Vision changes are virtually inevitable with increasing age. Loss of vision is a major obstacle to independent living which reduces the quality of life in old age. The initial phase of this project has extended our knowledge about vision function among the elderly and its relationship to vision task performance, subjective visual complaints and general health and functioning. Data on a wide array of vision functions have been gathered on 902 randomly selected,

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community-living participants over the age of 55 including an unusually large number, nearly 300, over 80 years, a subgroup whose vision function was essentially unknown. Many important goals of aging studies can now be addressed by the proposed longitudinal study for which the established study cohort, validated vision tests and concurrent epidemiologic study of health and functioning present a unique opportunity. The cohort will be tested twice more during the study period using the vision test battery, questionnaires (including the NEI Quality of Life instrument), and visual task performance measures. Driving and medical records will also be collected. An independently funded, longitudinal research program will be continued to evaluate general health, nutrition and physical functioning. This information in combination with the vision-related results will provide a data set unique in scope. Specific goals include characterization of the changes in vision function and visual task performance with age; determination of health, nutrition and other risk factors for loss of vision function; assessment of the ability of the vision measures to prospectively predict health status; and development of combined risk factor models to explain the synergistic interactions between vision and other health/functioning deficits in affecting everyday task performance and quality of life. The existing collaboration between Smith-Kettlewell Eye Research Institute and the epidemiological research program at the Buck Center for Research in Aging is a unique opportunity to address issues of broad scope and importance that would otherwise require enormous financial and human resources. At the same time, valuable data on vision changes with age will be made available on a population of rapidly increasing importance whose vision function has never before been comprehensively studied. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTOSOMAL DOMINANT EYE DISEASE: CATALYTIC RNA TREATMENT Principal Investigator & Institution: Lewin, Alfred S.; Professor; Molecular Genetics & Microbiol; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-JUL-1997; Project End 30-JUN-2006 Summary: (provided by applicant): The goal of this project is to develop a genetic therapy for autosomal dominant retinitis pigmentosa (ADRP). Retinitis pigmentosa is a type of inherited retinal degeneration caused by the death of rod photoreceptor cells. It affects about 1 person in 3500 and leads to a progressive loss of vision and ultimately blindness, usually over a period of decades. Mutations in over 30 genes lead to retinitis pigmentosa, but defects in the gene for rhodopsin, the major light-harvesting pigment of the rod cell, are the predominant cause of ADRP. These dominant mutations lead to a malfunctioning, mis-sorted, or poorly folded molecule that eventually kills the rod cell that makes it. Our underlying hypothesis is that reducing the expression of these mutated forms of rhodopsin can rescue rod photoreceptors and preserve vision. The genetic tool we will employ for this purpose is a catalytic RNA molecule or ribozyme. Small ribozymes can be engineered to sever almost any RNA in a sequence-specific manner. The instrument we use to introduce the ribozymes into retinal cells is recombinant Adeno-Associated Virus or AAV. During the current funding period, we have designed ribozymes specific for mutant rhodopsin mRNA present in transgenic rat models of ADRP. When delivered to animals bearing the P23H rhodopsin mutation, these hammerhead and hairpin ribozymes protected photoreceptors structurally and functionally for up to 8 months. In this proposal, we describe plans to extend these promising results by improving the ribozymes and the AAV vectors that deliver them; by testing the therapy in a large animal model of ADRP (transgenic pigs); by developing

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allele-independent ribozymes to treat a variety of rhodopsin mutations; by employing novel RNA catalysts to increase the number of potential target sites in rhodopsin mRNA; and by evaluating gene therapy in outbred mice carrying the P23H mutation. This work will be aided by non-invasive analytical techniques that permit us to monitor retinal degeneration and the efficacy of therapy in living animals. We hope that the successful completion of this project will bring us close to employing AAV-vectored ribozymes as therapy for autosomal dominant retinitis pigmentosa in human patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CADHERIN REGULATION OF AQUEOUS HUMOR OUTFLOW Principal Investigator & Institution: Stamer, W Daniel.; Associate Professor; Ophthalmology; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: Glaucoma, the second leading cause of irreversible blindness in the United States, is a group of disorders characterized by progressive loss of retinal ganglion cells with associated loss of vision that is in most cases coincident with elevated intraocular pressure (IOP)1-3. Today and in the foreseeable future, those with glaucoma are managed clinically with pharmaceutical agents that control IP. Elevated IOP in those with glaucoma appears to be a function of defective regulatory processes mean to maintain normal IOP that result in increased resistance to outflow/4-7. A current area of focus for glaucoma research is to understand the molecular and cellular mechanisms that underlie the regulation of aqueous outflow resistance. In the present proposal, we examine the regulation of aqueous humor in the outflow pathway in a novel manner. We will study a family of transmembrane cell-cell adhesion molecules, the cadherins, in the cells of the human outflow pathway. Cadherins form adheren function complex that in the outflow pathway have only been described at the morphological level. Since homophilic protein:protein interactions of the extracellular domains of cadherins on adjacent outflow cells are critical in the integrity of intercellular junctional complexes (including adherens, occludens and gap), we hypothesize that cadherens contribute significantly to the generation of outflow resistance Our study will examine these proteins at the molecular level and a) identify the subtypes present in both TM and SC cells (normal and glaucomatous), b) analyze effects of pressure/flow on relative expression levels, subcellular distribution and turnover and c) monitor signaling molecules that regulate the formation and remodeling of proteins in the adheren complex. If successful, results obtained from these investigations will provide a basic understanding of the role of cadherin subtypes in aqueous outflow resistance, uncover novel therapeutic targets for glaucoma therapy and generate a foundation for future investigations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CANDIDATE GENES FOR PRIMARY OPEN ANGLE GLAUCOMA Principal Investigator & Institution: Hauser, Michael A.; Assistant Research Professor; Medicine; Duke University Durham, Nc 27710 Timing: Fiscal Year 2002; Project Start 02-JUL-2001; Project End 30-JUN-2006 Summary: (provided by applicant): Glaucoma is one of the leading causes of blindness in America, and affects over 15 million individuals. Loss of vision is caused by degeneration of the optic nerve, often accompanied by elevated intraocular pressure. There is a large genetic component to this disease, but the specific genes involved are not yet known. Current treatments are aimed at slowing vision loss by reducing

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intraocular pressure, but do not address the molecular basis of the disease. The goal of this project is to investigate differential gene expression in the trabecular meshwork, in order to identify genes that affect the drainage of fluid, and in turn, intraocular pressure. We hypothesize that the abnormal functioning of trabecular meshwork tissue in patients with primary open angle glaucoma (POAG) is associated with altered patterns of gene expression in this tissue. We will use Serial Analysis of Gene Expression (SAGE) to profile transcription patterns in trabecular meshwork from POAG patients as well as from young (20-40 years) and age-matched (50-70 years) controls. Genes whose expression levels are significantly up- or down-regulated in affected individuals will be investigated as candidate genes for POAG. We will also investigate genes whose expression levels changes significantly with age in normal individuals. These genes will be mapped, providing an excellent resource for future positional cloning of disease genes that affect the trabecular meshwork. Candidate genes will then be tested for association with POAG by family-based association analysis. This double screendifferential expression in affected tissue and statistical association with disease-will provide a powerful mechanism for the identification of candidate susceptibility genes. The most promising candidates will then be characterized at the molecular level and screened for mutations and polymorphisms. The identification of POAG susceptibility genes could provide the basis for diagnostic tests and lead to earlier detection of POAG and a greatly improved prognosis for the millions of patients affected with this debilitating disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ELASTIC FIBER DEFECTS IN PSEUDOXANTHOMA ELASTICUM Principal Investigator & Institution: Boyd, Charles D.; Professor and Research Director; None; University of Hawaii at Manoa Honolulu, Hi 96822 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: The aim of this proposal is to understand the biological and pathogenetic basis of elastic fiber defects in a heritable disorder of cutaneous, vascular and ocular tissue, pseudoxanthoma elasticum (PXE). PXE is a heritable disease characterized by the accumulation of abnormal elastic fibers in several elastic tissues, particularly the skin, arteries and the elastic Bruch's membrane of the retina. The aberrant deposition of calcified elastic fibers in these tissues is responsible for the development of the clinical symptoms characteristic of PXE and these include inelastic skin lesions, retinal hemorrhage with partial loss of vision and vascular defects such as gastrointestinal bleeding and myocardial infarction. The pattern of inheritance of PXE is complex and both autosomal dominant and recessive forms of the disease have been reported. Over the last few years, several groups of investigators have attempted to identify the gene mutation(s) responsible for PXE but it has only been in the last two years that three separate laboratories, including our own, have located a major locus for this disease on the short arm of chromosome 16. We have now successfully identified a region at 16p13.1 of 820kb that contains 6 candidate genes, at least one of which will contain the mutations responsible for PXE. With this new information, we hope to identify the 'PXE gene', the mutations in this gene in a cohort of PXE patients and determine a possible function for the product of the PXE gene. These goals are focused on elucidating the biology of PXE and using this information to provide a better understanding of the role of elastic fibers in more common elastic tissue diseases, particularly those skin, vascular and eye disorders characterized by tissue calcification such as the many dystrophic calcification disorders of skin, aneurysms, atherosclerosis and age-related macular degeneration.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FRAGMENTS OF TRPRS TO TREAT NEOVASCULAR EYE DISEASES Principal Investigator & Institution: Friedlander, Martin; Associate Professor; Scripps Research Institute Tpc7 La Jolla, Ca 92037 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis. Pathological retinal or choroidal neovascularization lead to visual loss in diabetic retinopathy (DR) and age related macular degeneration (ARMD), respectively. While inhibition of abnormal angiogenesis would not necessarily cure the underlying diseases, it would preserve vision by preventing complications associated with neovascularization such as hemorrhage and edema. We have been studying the anti-angiogenic activity of fragments of tryptophanyl-tRNA synthetase (TrpRS). In normal human cells TrpRS exists as both the full length form and a truncated form (mini-TrpRS) in which an amino-terminal domain is deleted due to alternative splicing of the pre-mRNA. This latter form is preferentially synthesized in cells exposed to interferon-w. Further truncation of mini-TrpRS results in a 42 kD form (T2) that is the most potent of the angiostatic forms of TrpRS evaluated to date. In this application we propose to further characterize the anti-angiogenic activity of TrpRS fragments and identify a candidate drug and delivery system for use in clinical trials of neovascular eye diseases. Specifically, we will: (1) examine the physiological role of TrpRS fragments in the regulation of normal and abnormal ocular angiogenesis; (2) identify and characterize the retinal receptor to which these fragments bind; (3) characterize the structural aspects of TrpRS fragments with anti-angiogenic activity and use this information to model small molecular antagonists with similar activity; (4) develop viral-, cell- and targeted liposome-based vectors for the delivery of T2 to inhibit ocular neovascularization in a variety of animal models; and (5) begin pharmacokinetic and toxicology studies on these vector, recombinant protein and/or small molecule therapeutics as a first step towards human clinical trials for the treatment of neovascular eye diseases such as neovascular ARMD, proliferative DR and rubeotic glaucoma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE EXPRESSION ANALYSIS IN MICROCAPTURED RETINAL CELLS Principal Investigator & Institution: Adler, Ruben; Arnall Patz Distinguished Professor; Ophthalmology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-MAR-2006 Summary: (provided by applicant): Retinal degenerative diseases are a major cause of visual disability and blindness worldwide. Age-related macular degeneration (AMD), for example, is the leading cause of blindness in the elderly in the Western world. Current treatments do little to alter the inexorable loss of vision due to retinal degenerations. Several studies have shown that intraocular injection of factors such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), or basic fibroblast growth factor-2 (FGF2), slows photoreceptor cell death caused by specific mutations or exposure to constant light. However, the clinical usefulness of these findings may be limited, because rescue effects are partial and transient, and some factors appear to have unwanted side effects. Elucidation of the mechanism by which survival factors delay retinal degenerations appears necessary in order to maximize

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benefits and minimize side effects. Recent studies from our laboratories have suggested that CNTF, BDNF and FGF2 do not act directly on photoreceptors; rather, they appear to act indirectly through other cells, most likely M
ller cells. Based on these observations, we propose to investigate the molecular changes triggered by neurotrophic factors in M
ller cells. The studies involve the combined use of two complementary and demanding state-of-the-art techniques: the generation of cDNA from individual cells, and their analysis using custom designed retinal cDNA microarrays. We will then establish which of these changes are important for photoreceptor survival. The potential impact of the identification of these molecules is clear, since they could offer new avenues for the treatment of these devastating diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR RETINAL DETACHMENT Principal Investigator & Institution: Tomasek, James J.; Professor & Vice Chair for Research; Cell Biology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2003; Project Start 16-JAN-2003; Project End 31-DEC-2005 Summary: (provided by applicant): Retinal detachment with subsequent loss of vision is a major clinical problem associated with a number of ocular diseases, including proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). Surgery, the only treatment currently available, has a high rate of recurrence of fibrous epiretinal membrane formation and retinal detachment. Smooth muscle (SM) alphaactin containing myofibroblasts are a major cell type present in the epiretinal membranes that form in PVR and PDR and it is these cells that are responsible for generation of force leading to retinal detachment. The long-term goal of this research is to develop a gene therapy-based approach that targets and blocks the contraction of the myofibroblast. The first objective of this project is to develop a myofibroblast-specific promoter. Recent studies have suggested that the regulation of SM alpha-actin expression is different in myofibroblasts and smooth muscle cells and these studies have begun to identify regulatory elements in the promoter bf SM alpha-actin that might be responsible for these differences. Therefore, the first specific aim is to identify regulatory elements within the SM alpha-actin promoter that are specific to myofibroblasts in epiretinal membranes. To address this aim we will use transgenic mice containing a SM alpha-actin promoter/LacZ transgene in which specific regulatory elements have been deleted or mutated. These mice will be mated with a transgenic mouse model in which an epiretinal membrane containing myofibroblasts forms and contracts, with subsequent retinal detachment. The second part of our long-term goal is to be able to block the contraction of myofibroblasts in the epiretinal membranes. The expression of SM alpha-actin in myofibroblasts is functionally related to the ability of these cells to generate large amounts of contractile force. Therefore, the second specific aim is to determine whether knocking out the SM alpha-actin gene will decrease or inhibit retinal detachment. Specifically we will determine the length of time it takes for retinal detachment to occur in control and SM alpha-actin-null mice. These studies will provide the basis for developing a gene therapy-based approach that can specifically target myofibroblasts in epiretinal membranes and block their generation of contractile force thereby blocking epiretinal membrane contraction and retinal detachment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS OF AGE RELATED MACULAR DEGENERATION Principal Investigator & Institution: Klein, Michael L.; Professor; Ophthalmology; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-AUG-1998; Project End 31-JUL-2003 Summary: Age-related macular degeneration (AMD) is recognized as the leading cause of blindness in the United States. It affects nearly 1.5 million older Americans and causes loss of vision in more than 7 percent of individuals over 75 years of age. Currently, there are no established means of preventing AMD. The only proven effective treatment, laser photocoagulation, is successful in only a small proportion of cases. While the etiology of AMD is unknown, there is considerable evidence implicating a strong genetic component for the disease. Advances in genomic screening and analysis methodologies make a direct genetic approach to the etiology, pathophysiology, and ultimate therapy of AMD viable. Recent successes with other complex traits, which share genetic and epidemiological similarities with AMD, support the idea that identification of genetic loci responsible for AMD is an achievable goal. The long-term objectives of this project are to identify genes responsible for AMD, develop diagnostic tools to identify patients at risk of developing the disease, and to understand its molecular pathophysiology. This understanding will allow the development of preventive measures and improved methods of treatment. The immediate goal of this research proposal is to map genetic loci cosegregating with AMD in a number of affected families. We will employ both parametric and several nonparametric linkage analysis methods. To achieve these goals, we propose to: 1) Continue to collect additional kindreds containing multiple affected living members; 2) Complete genomewide screening of AMD families, beginning with a set of candidate loci; 3) Fine-map loci suggestive of linkage and conduct detailed multi- point parametric and nonparametric linkage analysis; and 4) Refine identified loci and begin studies to identify the specific genetic defects responsible for AMD in these families. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS OF AGE-RELATED MACULOPATHY Principal Investigator & Institution: Gorin, Michael B.; Associate Professor; Ophthalmology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-1993; Project End 31-JUL-2006 Summary: (provided by applicant): Age-related maculopathy (ARM) is the leading cause of irreversible blindness in the elderly population and heredity is clearly the most important risk factor. Treatment for this group of conditions is extremely limited and primarily focused on minimizing the further loss of vision in patients with advanced disease. The long range objective of this project is to identify the genetic contributions to age-related maculopathy (ARM). The goal is to better understand the causes of this condition so that eventually preventive therapies can be developed and tested in at-risk individuals. We have established a rigorous diagnosis scheme for ARM, screened a series of 12 candidate loci, completed two autosomal 10 cM genome-wide scans on a total of 400 ARM families, and, by the end of the current funding period, will have completed a third 10 cM genome-wide scan on an additional set of 200 ARM families. We have one of the largest datasets of ARM families in the world for molecular genetic studies. While we are preparing to undertake our final genome-wide scan of ARM families with CIDR, we are initiating the investigation of the six regions of potential linkage that we have already identified. We will collect additional ARM families, as well

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Loss of Vision

as sporadic ARM cases and matched controls (from spouses) for additional testing using linkage and association methods. Microsatellite genotyping of ARM families will be done to further refine potential regions of interest. We will then use single nucleotide polymorphisms (SNPs) and association methods to study the two most promising regions that contain genes involved in ARM. From these studies, we can then proceed to evaluated individual candidate genes for their potential role in this condition. We will also use our large set of ARM subjects, families and controls to test candidate genes that are tentatively identified from other research studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPITHELIUM

HOMEOSTATIC

ABILITY

OF

THE

RETINAL

PIGMENT

Principal Investigator & Institution: Wildsoet, Christine F.; Professor; Optometry; University of California Berkeley Berkeley, Ca 947205940 Timing: Fiscal Year 2002; Project Start 01-FEB-1978; Project End 31-AUG-2003 Summary: (provided by applicant): The retinal pigment epithelium (RPE) lies in the back of the eye between the neural retina and its choroidal blood supply. This layer of epithelial cells serves to protect the health and integrity of the outer retina. In the choroid, abnormal blood vessel growth or choroidal neovascularization (CNV) occurs in diseases such as age related macular degeneration (AMD) - the major cause of blindness for people over the age of 60. Vascular endothelial growth factor (VEGF) and other proor anti-angiogenic factors are constitutively secreted by the RPE into the extracellular space on both sides of the epithelium. The effects of these molecules on RPE physiology are not known. Evidence from human pathologic specimens and from rodent models suggests that increased VEGF production by the RPE is the source of CNV. Research in this area is severely hampered by the lack of a small animal model in which VEGF secretion by the RPE induces CNV. In preliminary experiments, we have used gene transfer techniques to develop a rat model for stimulating blood vessel growth in the back of the eye. This model will be used to test the hypothesis that secretion of VEGF by RPE is critically important in generating choroidal neovascularization (CNV). Gene transfer techniques will be also used to inhibit or reduce this VEGF-induced abnormal blood vessel growth. These experiments should provide a deeper understanding of CNV and the basis for a potential therapy for diseases like AMD. Normally, there is a very close anatomical relationship between the RPE and the retina. Separation of these two tissues occurs in a whole host of pathologies that lead to the abnormal accumulation of fluid in the extracellular or subretinal space. This separation or retinal detachment can lead to a loss of vision. One of our goals is to develop a rat model of retinal detachment. This model will allow us evaluate putatively therapeutic molecules that work directly on the RPE to remove fluid from the subretinal space. This removal will restore the normal anatomical relationship between RPE and retina and should improve vision. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HYPERSPECTRAL IMAGING OF OXYGEN SATURATION IN THE ONH Principal Investigator & Institution: Khoobehi, Bahram; Professor; Ophthalmology; Louisiana State Univ Hsc New Orleans New Orleans, La 70112 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006

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Summary: (provided by applicant): The development of a non-invasive means of measuring oxygen saturation in the fundus of the human eye would be useful in the diagnosis and monitoring of numerous disorders, including diabetic retinopathy, arterial venous occlusion disease, and glaucoma. In these studies, a practical system to evaluate oxygen saturation in the retina and optic nerve head using a recent innovation, hyperspectral imaging, will be developed. The hyperspectral technique measures spectral changes within the visible and infrared spectra and provides information on the molecular state of hemoglobin. The hyperspectral imaging device will allow measurement - non-invasively and in real time - of reduction and/or elevation in tissue oxygenation. The distinct optical signature of biological materials such as oxyhemoglobin and deoxy-hemoglobin as a function of their reflectance spectra will enable determination of their relative concentrations. In recent years, reflectance oximetry has been developed for the non-invasive measurement of oxygen saturation changes in the vessels of the fundus using double, triple, and multiple wavelength reflectance imaging. The hyperspectral reflectance oximetry that will be employed in these studies will permit the first non-invasive measurement for oxygen saturation in the optic nerve head tissue, and the hyperpectral data to be collected will intrinsically include all of the multiple wavelength spectra obtained in earlier approaches. The new system will be tested in two specific aims: 1) hyperspectral imaging will be used to non-invasively evaluate the stimulus-response relationship between perturbations in intraocular pressure (lOP) (10-50 mm Hg) and oxygen saturation in optic nerve head tissues and in retinal artery/vein pairs for a graded series of hypoxic states, and 2) the same studies will be performed in eyes with early stage experimental glaucoma. With this new approach, it will be possible to determine how acute changes in lOP alone or in combination with chronic lOP elevation (glaucoma) affect the three distinct microcirculations of the optic nerve head (surface nerve fiber layer; prelaminar region; lamina cribrosa) independently and/or collectively. The proposed studies are motivated by the potential for clinical application of this innovative technology in the early diagnosis of and monitoring of therapy for ocular vascular diseases in which the associated hypoxia may eventually lead to loss of vision. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFYING AND REDUCING ERRORS WITH SURGICAL SIMULATION Principal Investigator & Institution: Fried, Marvin P.; Montefiore Medical Center (Bronx, Ny) Bronx, Ny 104672490 Timing: Fiscal Year 2002; Project Start 27-SEP-2001; Project End 31-AUG-2004 Summary: The training of a surgeon requires the acquisition of a number of characteristics. These include a knowledge base (cognitive), problem formulation, decision processing, psychosocial relationships and others that can be evaluated and graded by objective testing such as National Board or Specialty Certifying examinations. Critical to the surgeon are the technical skills that are at the core of the profession. This proposal responds to the need to create a battery of sophisticated devices and objective measurements to teach and evaluate the inherent technical ability of trainees. We hypothesize that by innovative, state- of-the-art simulation, devices that train both surgical tasks and skills through repetitive proctored challenges, without risk to patients, will allow for detection and analysis of surgical errors and "near misses". In an analogy to flight simulation, "near miss" detection is where potential errors are found and complications prevented Using a number of otolaryngology residencies, a controlled training curriculum will be developed based on complimentary simulation

14

Loss of Vision

tools [the endoscopic sinus surgery simulator (ES3), minimally invasive surgical trainer virtual reality (MIST VR), perceptual and 3- dimensional testing] with objective metrics used for assessment of trainees. Technical errors will be identified, quantified and used to train and monitor surgical performance and for outcomes analysis to improve patient safety. Some current validated metrics include: time- to-completion, errors, economy of motion and psychomotor tracking. Correlation with psychometric parameters (perception, psychomotor, visio-spatial, cognitive mapping, etc.) will be used to identify technical errors and to validate both the simulator and the curriculum. The collaborating investigators and institutions have expertise in the areas of metrics, curriculum, database development, simulator creation and modification, and outcomes analysis. Endoscopic sinus surgery is the operation substrate since it is frequently performed (greater than 300,000 procedures annually) and carries a significant risk of injury to the contiguous structures ofthe eye (loss of vision and /or eye motion) and brain (CSF leakage, meningitis, death). The ES3 is also the most advanced surgical simulation device existing and based largely on jet pilot flight simulation (Lockheed Martin). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERACTION OF HSV-1 LAT GENE & DENDRITIC CELLS FUNCTION Principal Investigator & Institution: Benmohamed, Lbachir; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-AUG-2002 Summary: (Applicant's Abstract): Ocular HSV-1 is a leading cause of corneal blindness due to an infectious agent. Our long term goal is to understand how HSV-1 evades the immune response thereby enhancing latency and recurrent disease even in the face of local and systemic immunity. The antigen presenting dendritic cells (DC) play a central role in initiation and modulation of local and systemic immunity. HSV-1 can infect DC and interfere with their maturation (a process critical to DC function). This may help HSV-1 evade the host immune response. As the only HSV-1 gene abundantly transcribed at all times, LAT is a candidate, for modulating DC activity during both acute and latent infection. Preliminary studies suggest that LAT can alter DC cytokine expression. Thus, LAT can affect DC. We hypothesize here that LAT is critical for HSV1's ability to interfere with DC maturation. We further hypothesize that HSV-1 can inhibit DC trafficking (another critical DC function), and that LAT is also critical for this viral activity. If correct, these hypotheses would reveal a novel immune evasion strategy and open new doors to novel immunotherapeutic interventions against acute and recurrent HSV-1 infections. This would lead to the development of methods to greatly alleviate suffering and loss of vision due to recurrent ocular HSV-1. Our Specific Aims include: 1. Determine if the ability of HSV-1 to interfere with DC maturation is due to LAT. In vitro and in vivo studies will be done to determine if infection of DC with HSV1 LAT+, but not HSV-1 LAT-, will block membrane expression of MHC and costimulatory molecules, and inhibit HSV and non-HSV antigen presentation by DC. The ability of plasmids expressing LAT to block MHC and co-stimulatory molecule expression and inhibit antigen presentation will also be examined. 2: Determine if LAT alters DC migration. (a)Determine if LAT modulates cytokine and chemokine secretion by DC and chemokine-receptor expression on DC, all of which are involved in migratory activity of DC. (b)Determine if LAT changes the observed migratory activity of DC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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15

Project Title: NEURAL RESCUE AND REPLACEMENT IN GLAUCOMA Principal Investigator & Institution: Jhaveri, Sonal; Principal Research Scientist; Brain and Cognitive Sciences; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 28-FEB-2006 Summary: (provided by applicant): Glaucoma is a disease that affects millions of people worldwide, and for which there is no cure. The major focus of current strategies for glaucoma management is to preserve the vision that remains at the time of diagnosis. In afflicted eyes, retinal ganglion cells (RGCs) are lost, leading to an irrevocable loss of visual function. However, with the discovery of neural stem cells (NSCs), and with the finding that stem cells exist in the ciliary margin of the adult retina, the promise of RGC rescue/replacement, along with recovery of visual function, has becoming increasingly real. The ultimate goal of the work outlined here is intended to help develop a clinical means of restoring normal vision in human glaucoma patients. Using rodent models of glaucoma and RGC apoptosis (the type of cell death seen in glaucoma), we propose a multi-pronged approach that employs NSCs to rescue and replace sick or dead RGCs; we will also use axogenic factors in combination with NSCs to stimulate axon extension from the rescued or replaced neurons. Our pilot observations suggest that one of the NSC lines that we have used may provide trophic support to dying RGCs -these cells will be applied towards rescuing RGCs whose axons have been damaged. A second cell line has reportedly been used successfully to replace damaged retinal neurons (including RGCs) in dystrophic and mechanically damaged eyes; our aim is to use this second type of NSC to replace RGCs in glaucomatous eyes. In addition, specific neurite growth-inducing molecules or surgical manipulations that we have found to induce fiber extension, will be used to stimulate long distance axon projections from replaced RGCs. These experiments will be complemented with similar studies using stem cells harvested from the retina itself. The proposed studies will reveal the potential for using NSCs and axon-growth promoting molecules to reverse loss of vision in glaucomatous eyes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: OCULAR SURFACE HISTATINS: SYNTHESIS AND FUNCTION Principal Investigator & Institution: Steele, Pamela S.; Ophthalmology and Visual Scis; University of Louisville Jouett Hall, Belknap Campus Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (Applicant's Abstract) Histatins are small cationic peptides present in human saliva which exhibit potent antifungal properties and contribute to the non-immune (innate) protection of the oral mucosa. Structural, embryological, and functional similarities shared by oral and ocular mucosal membranes suggest the development of common antimicrobial defense strategies. Preliminary studies in this laboratory have, for the first time, demonstrated the presence of histatin in the both the conjunctiva and lacrimal gland. Diverse populations including the immunocompromised, diabetic and elderly patients are particularly susceptible to fungal infection of mucosal surfaces. These infections are often resistant to standard therapies and, in the case of the ocular surface, can lead to permanent loss of vision. Enhancement of innate mucosal defense capabilities is therefore a potentially effective strategy for controlling and combating such infections. We propose to identify and quantify the-histatin in tear film by mass spectroscopy. In situ hybridization of ocular tissues will allow for-the localization of histatin transcripts. Cytokine and microbial challenge to human conjunctival cells and

16

Loss of Vision

subsequent quantification of histatin transcripts by competitive PCR will identify the regulatory mechanisms of histatin transcription. Lastly, we will quantify salivary and lacrimal histatin from Sjogren's patients in order to determine the effect of autoimmune destruction of glandular tissue on the abundance of this antifungal peptide. These studies will contribute to the development of innovative therapeutic strategies to combat fungal infection in ocular tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PAX-6 AS A KEY REGULATOR OF LENS DEVELOPMENT Principal Investigator & Institution: Cvekl, Ales; Ophthalmology and Visual Scis; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-JAN-2000; Project End 31-DEC-2004 Summary: (from abstract): The long-term goal of this application is to identify those interactions between Pax-6 and other transcription factors that are required for normal lens development and transparency. Pax-6, a paired domain and homeodomain containing transcription factor, is essential for lens formation and function. Mutations in Pax-6 cause several human ocular diseases: aniridia, Peter's anomaly, autosomal dominant keratitis, foveal hypoplasia, and some forms of cataract. These defects lead to loss of vision. It is recognized that lens refraction and transparency depend on the accumulation of high concentrations and short-range interaction of multifunctional proteins, the crystallins. Recent in vivo studies demonstrated that missexpression of crystallins can lead to lens opacification resulting in cataracts. In order to carry out this long term goal of this project the following specific aims are proposed,-. (1) To identify and functionally characterize general trancription factors that interact with and mediate the transcriptional activity of Pax-6; (2) To identify and functionally characterize other DNA binding and non-DNA binding transcription factors that synergistically interact with Pax-6. These specific aims will be achieved using an integrative approach involving functional in vitro (transcription using recombinant factors and nuclear extracts) and in vivo (transfections of cultured lens and non-lens cells) studies combined with proteinDNA binding assays using recombinant proteins and lens nuclear extracts, and proteinprotein interactions studied in solution and on a solid matrix. The feasibility of the proposed study is demonstrated by preliminary data demonstrating those lens crystallin genes which are targets for Pax-6, identifying those other transcription factors that act in conjunction with Pax-6 (e.g. retinoic acid activated nuclear receptors), and by demonstrating the function of crystallin promoters fused to reporter genes in both transfected lens cells and in transgenic mice. Collectively, these studies form the basis for a functional model of Pax-6 mediated gene regulation that applies to both crystallin gene regulation and noncrystallin genes expressed in the lens. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PHARMACOLOGICAL NEUROPROTECTION IN GLAUCOMA Principal Investigator & Institution: Neufeld, Arthur H.; Senior Scientist; Ophthalmology and Visual Sci; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-JUL-1998; Project End 30-APR-2004 Summary: Primary open-angle glaucoma and normal pressure glaucoma are sight threatening, age-related, eye disease that are often associated with intraocular pressure (IOP). Current treatments of the diseases are based on lowering the IOP, by pharmacological or surgical means, to prevent further degeneration of the optic nerve

Studies

17

and loss of vision. Recent investigations on the cellular basis of neuronal degeneration in general, and the optic nerve in particular, have led to speculation that therapies directly aimed at preventing, slowing or reversing glaucomatous optic neuropathy can be developed. The long-term objective of this work is the identification of a class of compounds that could be developed as a pharmacological neuroprotective agents for the treatment of patients with glaucomatous optic neuropathy. Significant observations, made by this laboratory in human glaucomatous tissue, have described the presence of NOS-1, -1, -3, as well as COX-1 and -2, in the optic nerve head. Some of these pathways may contribute to neurodestruction in this tissue. The completion of the proposed specific aims: 1) identification of which isoforms of nitric oxide synthase (NOS) and cyclooxygenase (COX) pathways are upregulated or induced in human glaucomatous optic neuropathy, 2) demonstration of these specific pathways in the rat eye during optic nerve degeneration, and 3) study of the pharmacological inhibition of these specific pathways in a rat model of elevated IOP, will advance the development of the next generation of drugs to treat glaucoma. The proposed investigations are designed to first extend the observations in humans, by using immunohistochemistry, in situ hybridization, and reverse transcriptase-polymerase chain reaction, so that specific isoform pathways can be targeted for study in the rat. In the rat, optic nerve degeneration will be modeled using three approaches: chronic, moderately elevated IOP by three scleral vessel cautery, retinal ischemia by acute elevated IOP, and optic nerve transection. Specific pharmacological intervention will be tested in the rat model against NOS and COS isoform pathways that are identified in human glaucomatous tissue and potentially contributing to neurodestruction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHYSIOLOGY AND PATHOPHYSIOLOGY OF PHOTORECEPTORS Principal Investigator & Institution: Kraft, Timothy W.; Physiological Optics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-APR-1994; Project End 31-MAR-2005 Summary: Retinal degeneration is a major cause of blindness in our elderly population as well as the tens of thousands of younger Americans afflicted with inherited retinal degenerations such as retinitis pigmentosa (RP). Photoreceptor degeneration is a final common pathway resulting in loss of vision for many insults to the eye, including many mutations of rhodopsin or other proteins of the phototransduction cascade. In retinal degenerations caused by mutations in rod-specific genes, it is equally important to comprehend why the normal cone photoreceptors also die bringing patients from night blindness to near total blindness. We propose experiments on two newly characterized animal models of autosomal dominant retinitis pigmentosa, the transgenic pig carrying mutant rhodopsin. This grant will answer three important questions: (1) How do the P347L and P347S rhodopsin mutations alter normal phototransduction and rod signaling? (2) How do electrophysiological recordings of single cell photoresponses compare to those same responses derived by indirect methods with the electroretinogram (ERG)? This project will document the ERG's capacity as a tool used to probe photoreceptor function. Massive loss of rod photoreceptors in these animals and in patients with RP somehow kills the cone photoreceptors as well. If cone function could be rescued, a substantial portion of human visual behavior would remain intact. (3) What are the pathologic changes in the physiology of cone photoreceptors associated with retinal degeneration due to rhodopsin mutations in the pig? The past decade has seen tremendous advances in the understanding of the biochemistry and molecular biology of phototransduction, yet little is known about photoreceptors pathophysiology.

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We will investigate the single cell photocurrents with the suction electrode technique to examine the changes that take place throughout the course of the retinal degeneration and loss of vision. Several biophysical parameters of the rods and cones will be measured at 3 to 5 stages over a period in which all the rods and half the cones are lost. We will also examine the photoreceptor responses to flickering light which is predicted to be a sensitive indicator of cell health. Statistical analyses will determine major and minor effects. We will establish a quantitative physiological database for photoreceptor function in a degenerating retina coordinated with ERG evaluations of the retina at the same stages of disease. This data base will be useful in judging therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RETINOPATHY PATHOGENESIS

OF

PREMATURITY:

UNDERSTAND

ITS

Principal Investigator & Institution: Penn, John S.; Professor; Ophthalmology and Visual Scis; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-APR-1988; Project End 30-JUN-2005 Summary: New developments in neonatal technology have resulted in the survival of smaller infants who have limited retinal vascular development at birth and, thus, greater susceptibility to retinopathy of prematurity (ROP). It is reasoned that as more and smaller premature babies survive, the incidence of visual loss from ROP will continue to increase unless effective treatments are found. Advanced ROP is characterized by a period of unregulated growth of retinal blood vessels. This growth occurs by a process known as angiogenesis, indicating that the new vessels form by an abnormal sprouting of exiting vessels. The loss of vision from angiogenesis is not unique to ROP; collectively, ocular disorders with this feature constitute the leading cause of blindness in the U.S. The significance of research aimed at understanding retinal angiogenesis in an animal model of one of these diseases is amplified by the potential of applying the new knowledge to other ocular conditions in which angiogenesis plays a role. The ultimate goal of this project is to develop methods to prevent retinal angiogenesis based upon understanding gained from studies of relevant models. We propose to use pure cultures of retinal microvascular endothelial cells (RMEC), a well- established rat model of ROP and a mouse model of ROP currently under refinement. With these tools, we will address the following four interrelated aims: 1) investigation of the role of a pivotal tyrosine kinase, Src, in RMEC proliferation and tube formation and in ROP-related retinal angiogenesis; 2) characterization of the proteolytic aspect of ROP-related retinal angiogenesis, emphasizing PAI-1, MMP-2 and 9 and TIMP-2; 3) characterization of the roles of angiopoietins 1 and 2 in retinal vasculogenesis and angiogenesis; and identification of factors responsible for the angiostatic effect of penetrating ocular injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLES OF TOXINS IN ENDOPHTHALMITIS Principal Investigator & Institution: Gilmore, Michael S.; Vice President for Research; Microbiology and Immunology; University of Oklahoma Hlth Sciences Ctr Health Sciences Center Oklahoma City, Ok 73126 Timing: Fiscal Year 2002; Project Start 01-AUG-1989; Project End 29-SEP-2006 Summary: (provided by applicant): Endophthalmitis is one of the most sight-threatening complications of ocular surgery or penetrating injury. Despite aggressive therapeutic and surgical intervention, endophthalmitis frequently results in partial to complete loss

Studies

19

of vision, often within a few days of infection. The overarching goal of this research is to develop a scientific basis for management of endophthalmitis, based on the optimized use of antimicrobial and anti-inflammatory agents, toward enhancing the recovery of useful vision. The following specific aims of the proposed 5 year continuation period are designed, based on the results from the previous period of support, to advance this goal: Specific Aim 1: Determine the molecular basis of virulence for the most common etiology of endophthalmitis associated with visual loss. Specific Aim 2: Develop a murine model system that permits complete analysis of host and bacterial factors that contribute to the pathogenesis of endophthalmitis, and determine the basis for 1) differences in pathogenesis of endophthalmitis due to virulent and avirulent organisms, 2) differences in the pathogenesis of endophthalmitis when infection is acquired by anterior and posterior routes, and 3) the contribution of immune privilege to the pathogenesis of endophthalmitis and mechanisms by which this may be undermined by specific pathogens. Specific Aim 3: Resolve the current controversy surrounding the use of anti-inflammatory adjunctive therapies in endophthalmitis management, and test new specifically targeted therapies for their value in mitigating visual loss. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SOLUTE AND FLUID TRANSPORT ACROSS THE CONJUNCTIVA Principal Investigator & Institution: Candia, Oscar A.; Professor; Ophthalmology; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-DEC-2003 Summary: Ion pumps and cotransport systems in animal cell membranes maintain cellular ionic composition, transport electrolytes and fluid across epithelia and contribute towards the regulation of cell volume. Thus, it is reasonable to expect that ion pumps in the conjunctival epithelium should play a crucial role in maintaining an optimal tear film, a necessity for a normal functioning ocular surface. However, the transport properties of this epithelium, which interfaces with the tears, are virtually unknown. Therefore, this project will use electrophysiological, radio-labelled tracer and microspectrofluorometric techniques to characterize the transport functions of the rabbit conjunctiva. A thorough understanding of the basic physiology of this cell layer may be relevant to the design of future treatment modalities for dry eye syndrome - a disorder, affecting countless individuals worldwide, that can lead to the loss of vision. The PI will 1) determine the effects of biological activators (i.e., hormones, neurotransmitters, etc.) on macroscopic conductances across the rabbit conjunctival epithelium; 2) determine the nature of the Na+ absorptive process in the apical (tear-facing) surface of the epithelium; 3) complete the characterization of the C1- secreting mechanism; 4) determine the identity of electrically silent transporters that may be present, with emphasis on those usually associated with intracellular pH and cell volume regulation; and 5) determine the diffusional H20 permeability (Pdw) and osmotic permeability (Pf). From these studies the PI expects to be able to construct a model detailing whether this epithelium functions as a fluid secreting or absorbing epithelium. Based on this model, he will devise protocols to modify and possibly reverse the secretory/absorptive properties of the tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DYSTROPHY

THE

GENE

FOR

SCHNYDER'S

CRYSTALLINE

CORNEAL

Principal Investigator & Institution: Weiss, Jayne S.; Professor; Ophthalmology; Wayne State University 656 W. Kirby Detroit, Mi 48202

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Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2005 Summary: Schnyder's crystalline corneal dystrophy (SCCD; OMIM number 121800) an autosomal dominant disease in which there is abnormal deposition of cholesterol and lipid in the cornea resulting in opacification and loss of vision. The dystrophy may manifest early in life and clinical appearance includes central corneal opacification, subepithelial cholesterol deposition, mid- peripheral stromal opacification and/or arcus lipoides. SCCD has been mapped to the chromosome 1p36.2-p36.3 with a maximum multipoint lod score of 8.48 in the interval between genetic markers D1S214 and D1S503 using two large Swede-Finn kindreds from Massachusetts. Haplotype analysis suggested that the SCCD gene is located in the 16 cM interval between markers D1S2663 and D1S228. In the present application, we propose to identify the gene which is responsible for SCCD. To accomplish this goal we will: 1) continue to fine map the disease locus with several additional families that display SCCD. The new and the original two large families will also be typed for additional polymorphic markers that map in the disease interval to help narrow the locus; 2) examine potential candidate genes that map to the refined disease interval to search for polymorphisms and/or mutations that may give rise to SCCD. Sequence polymorphisms and/or mutations will be examined for co-segregation with SCCD in the families (NOTE! The defined region will be most likely completely sequenced by the time the grant is funded making it unnecessary to screen cDNA libraries for extended sequence information. Also, this means that the mutation screening can be accomplished by using genomic DNA as a starting material. The term "potential candidate" here means that we will first search for mutations in those genes whose function is known and which are biologically relevant candidates. If no mutations are found in these genes the search will continue to genes with unknown function that are located in the defined candidate interval); and 3) use microarray expression profiling to identify differences in the expression levels of cDNAs mapped to the candidate interval in corneal tissue samples between SCCD patients and controls. Identification of the gene at fault and the specific mutations responsible for SCCD phenotype will not only afford increased understanding about SCCD but may provide insight into lipid metabolism in the cornea and elsewhere. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF GK IN HSV-1 INDUCED CORNEAL SCARRING Principal Investigator & Institution: Ghiasi, Homayon; Cedars-Sinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2002; Project Start 09-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Recurrent infection of HSV-1 causes corneal scarring (CS) and is the leading cause of infectious corneal blindness in the United States. Passive transfer experiments have shown that antibody to HSV-1 glycoprotein K(gK) severely exacerbates CS in mice ocularly challenged with HSV-1. The gK antibody produces antibody dependent enhancement (ADE), which results in increased HSV-1 infectivity and higher viral load in the eye. This in turn leads to an increase of all immune responses examined in the eye, including the as yet undetermined immune response that directly causes exacerbation of CS. For whatever reason, protective immune responses, which are presumably also increased by gK antibody ADE, are not able to block the effect of the "harmful" immune response and CS is severely exacerbated. We hypothesize that: (a) In humans anti-gK antibody correlates with HSV-1 induced corneal scarring (CS), and (b) blocking anti-gK antibody will decrease corneal scarring (CS) (by blocking ADE). Our specific aims to test the above hypotheses are: (1) Confirm that antigK antibody correlates with CS in humans; (2) Map the gK epitopes that cause ADE and

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CS; and (3) Block anti-gK-antibody to decrease ADE and CS. If the studies proposed in this grant application confirm that gK antibody is involved in CS in humans, two exciting scenarios will be possible. (i) A method to interfere with or block anti-gK antibody could be developed (for example, blocking with gK peptides). This would decrease the severity of CS and subsequent loss of vision. (ii) Sera from HSV-1 seropositive individuals could be screened for anti-gK antibody titer and those with a high expected susceptibility to recurrent HSV-1 CS could receive prophylactic treatment (such as Acyclovir) even before their first incidence of severe recurrent disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: V1 TO V2 PROJECTIONS IN NORMAL VISION AND AMBLYOPIA Principal Investigator & Institution: Sincich, Lawrence C.; Ophthalmology; University of California San Francisco 3333 California Street, Suite 315 San Francisco, Ca 941430962 Timing: Fiscal Year 2002; Project Start 01-AUG-2002 Summary: In primates, visual information passes from the primary visual area (V1) to the second visual area (V2) before distribution to higher cortical areas. An accurate description of the projections linking V 1 and V2 is crucial for understanding how the brain deciphers visual images. Prior studies have shown that V2 is partitioned into three compartments, known as pale, thin, and thick stripes, defined by their content of a metabolic enzyme called cytochrome oxidase (CO). Our principal goal is to describe the anatomical projections from V1 to each V2 stripe compartment. In Specific Aim #1 we will make injections of a retrograde tracer into single CO stripes in V2 of normal macaques. The resulting pattern of labeled cells in V1 will be correlated with the V2 stripe that received the injection. Our preliminary data indicate that, contrary to a previous report, layer 4B and interblobs both project to thick stripes and pale stripes. In Specific Aim #2 we will make paired injections of two different tracers into adjacent thick stripes and pale stripes to determine if different subpopulations of cells in layer 4B and interblobs project to these V2 compartments. In Specific Aim #3 we will make injections of [3H]proline into V1 to correlate patches of efferent projections with CO staining patterns in V2. In Specific Ai/s #4 we will examine the V1->V2 projections in animals raised with early monocular deprivation. These experiments will advance our knowledge of the mechanisms underlying amblyopia, an important cause of visual loss that affects 2% of the American population. We hypothesize that a selective loss of V1>V2 projections emanating from the ocular dominance columns serving the deprived eye contributes to the loss of vision in amblyopia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VIDEO RATE OCT FOR EVALUATING GLAUCOMA Principal Investigator & Institution: De Boer, Johannes F.; Assistant Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2007 Summary: (provided by applicant): Glaucoma is the second leading cause of blindness worldwide. In the United States, approximately 2.5 million Americans are affected by this potentially blinding eye disease. Optical coherence tomography is the only noninvasive imaging technique allowing high-resolution cross-sectional imaging of the human retina. Since glaucoma causes thinning of the retinal nerve fiber layer prior to initial loss of vision, optical coherence tomograhy (which can measure the nerve fiber layer thickness) could enable early detection of glaucoma prior to any permanent loss of vision. This earlier detection would enable earlier treatment to prevent permanent loss

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Loss of Vision

of vision. Since glaucoma also causes progressive nerve fiber layer thinning prior to further loss of vision, optical coherence tomography could enable earlier detection of glaucomatous disease progression prior to further permanent loss of vision, enabling more aggressive preventive treatment. Current clinical techniques only allow diagnosis of glaucomatous loss of vision after up to half of the retinal ganglion cells are permanently lost. The overall goal of this research is A) to develop a video rate Optical Coherence Tomography (OCT) system for 3 dimensional high resolution imaging of the human retina and the retinal nerve fiber layer (RNFL), B) to determine the resolution and reproducibility of in vivo retinal nerve fiber layer thickness determination with video rate OCT in normal and glaucoma subjects, C) to correlate in vivo human OCT images with histology of the same eye. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: X-LINKED RETINITIS PIGMENTOSA Principal Investigator & Institution: Swaroop, Anand; Professor; Ophthalmology and Visual Sciences; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUL-1990; Project End 31-DEC-2005 Summary: (provided by applicant): The death of retinal photoreceptors as a result of genetic mutations or environmental abuse leads to irreversible loss of vision. X-linked retinitis pigmentosa (XLRP) is perhaps the most devastating of such diseases because of relative severity of phenotype and an early age of onset. Although several genetic loci have been mapped, a majority of XLRP can be accounted by RP3 and RP2 subtypes; the corresponding genes for the two loci, RPGR and RP2, respectively, have recently been isolated. RPGR and RP2 mutations have so far been identified in