FUNDING PERIOND: APRIL 1, 2002 - MARCH 31, 3003

Dennis O. Clegg, Ph.D.
University of California
Santa Barbara, California
Project: Regulation of Drusen Formation and Degradation in AMD

One of the hallmarks of age-related macular degeneration (AMD) is the formation of drusen deposits on the basement membrane underlying the retinal pigment epithelium (RPE). The loss of RPE, possibly caused by the presence of drusen, leads to the loss of photoreceptors, or light-sensing cells, and loss of vision. The mechanisms of drusen deposition and degradation are poorly understood. Dr. Clegg has hypothesized that matrix metalloproteinases (MMPs), enzymes that degrade proteins, are involved in the formation and degradation of drusen. It builds on an important observation that Sorsby's fundus dystrophy, a blinding disease that is similar to AMD, is associated with mutations of the enzyme tissue inhibitor of metalloproteinase-3 (TIMP-3). TIMP-3 is an inhibitor of MMP activity. Dr. Clegg has suggested that accumulation of TIMP-3, leads to inhibition of MMP activity and drusen accumulation. The goal of this study is to examine RPE cells that are in close proximity to drusen, as well as cells that are in remote areas of the retina not associated with drusen, and to determine the activity of MMPs and TIMP. The results of these experiments will allow future efforts to develop new treatments for AMD that either lessen drusen accumulation or bring about its removal.

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Mark Johnson, Ph.D.
Northwestern University
Evanston, Illinois
Project: Bioengineering Studies of Transport Across Bruch's Membrane

Clinical lesions of early age-related maculopathy (ARM) involve Bruch's membrane, a thin tissue layer between the small blood vessels in the choroid and the retinal pigment epithelium (RPE). It has been suggested that a decreased transport capacity of Bruch's membrane, perhaps due to lipid accumulation, may to be a critical early event in the pathogenesis of ARM. The decreased porousness of Bruch's membrane may lead to RPE detachment. This proposal seeks to understand the structural changes in the extracellular matrix of Bruch's membrane that accompany aging and that could alter transport across the membrane. Dr. Johnson is using quick-freeze/deep-etch (QFDE) technology that will provide insights into the transport capabilities of Bruch's membrane. QFDE preserves the extracellular matrix and allows structures to be visualized that are not seen in conventional transmission electron microscopy. Mathematical modeling is then being applied to the images of Bruch's membrane from QFDE analysis to evaluate the transport capabilities of Bruch's membrane and to evaluate the importance of lipids in altering the transport. In this study, Dr. Johnson is examining post-mortem, normal, donor eyes over seven decades of life. The results from this experiement will establish a baseline of data for normal tissue, and Dr. Johnson's future work will use diseased eyes. It is hoped that a better understanding of the pathophysiology of the early stages of ARM may help to guide the development of better treatments for the disease.

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Johanna M. Seddon, M.D.
Massachusetts Eye & Ear Infirmary
Boston, Massachusetts
Project: Biological Factors for Age-Related Macular Degeneration

The objective of this study is to test whether known biological markers of inflammation are correlated with the progression of age-related macular degeneration (AMD). Dr. Seddon hypothesizes that AMD is mediated, at least in part, by the same factors shown to be related to other age-related diseases, like atherosclerosis. These factors include chronic inflammation, oxidative processes and nutritional factors. Dr. Seddon is examining the levels of three inflammatory markers in serum, C-reactive protein, interleukin-6 and tumor necrosis factor. She will measure the level of these factors in the serum of 474 patients from the Age-Related Eye Disease Study (AREDS), sponsored by the National Eye Institute, and correlate them to the progression of AMD. Identifying circulating risk factors for AMD may constitute a useful means for screening for AMD in a clinical setting. It is also hoped that the identification of modifiable risk factors can lead to improved therapies and a possible prevention of this disease.

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Janet R. Sparrow, Ph.D.
Columbia University
New York, New York
Project: Macular Degeneration: The Role of A2E in RPE Atrophy

The death of retinal pigment epithelial (RPE) cells in age-related macular degeneration (AMD) precedes the degeneration of photoreceptor cells and the loss of vision. One factor that places RPE cells at risk is the accumulation of lipofucsin fluorophores. A major fluorophore of RPE lipofuscin is A2E, which may be responsible for light-mediated RPE cell death. Dr. Sparrow has hypothesized that with light exposure, A2E within the cells undergoes chemical changes that produce reactive intermediates, which cause cell injury. Furthermore, she has proposed that the target of these reactive intermediates is cellular DNA. To test her hypotheses, Dr. Sparrow is using an RPE cell culture model in which the intracellular levels of A2E can be manipulated and the DNA can be analyzed. The goal of this work is to develop therapies that would reduce the formation of A2E, destroy this molecule within the RPE cell, or prevent the events initiated by A2E that cause cell damage. The accumulation of A2E in RPE is particularly relevant to atrophic (dry) AMD, and if successful, this study could provide a basis for the development of a treatment for the dry form of the disease.

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Kang Zhang, M.D., Ph.D.
The Cleveland Eye Clinic
Cleveland, Ohio
Project: Gene Mapping for Stargardt's Macular Degeneration

Stargardt's macular dystrophy (STGD) is a common childhood onset form of macular dystrophy characterized by the progressive loss of central vision during the first and second decades of life. STGD has been genetically linked to age-related macular degeneration (AMD). Dr. Zhang is performing a genetic study of three large families affected with STGD to identify the underlying disease-causing gene(s). His preliminary data excluded any known genes previously associated with STGD as playing a role in the disease in these families. He is now continuing his investigation using standard genomic methodology to identify new gene(s) that may be involved in Stargardt's macular dystrophy. The identification of new genes that are responsible for a disease is a key step towards understanding its pathogenesis. The natural history and clinical features of the disease can then be investigated for diagnostic purposes. The discovery of these genes will also help to identify family members that might be at risk for the disease before it strikes and provide information for designing new treatments.