FUNDING PERIOND: APRIL 1, 2003 - MARCH 31, 2004

Esther E. Biswas-Fiss, Ph.D.
Thomas Jefferson University
Philadelphia, Pennsylvania
Project: Molecular Analysis of ABCR Mutations

Advances in molecular genetics have led to the discovery and identification of genes and genetic mutations that are linked to various visual diseases. Recently, human genetic studies have correlated mutated forms of a retina-specific gene called the ATP binding cassette protein (ABCR) with several inherited visual diseases, including Stargardt's macular dystrophy, fundus flavimaculatus, age-related macular degeneration, retinitis pigmentosa, and cone-rod dystrophy.
The ABCR protein is a transporter protein that plays an important role in retinal rod and cone cells, where it is believed to function in the transport of retinaldehyde. Many of the disease-associated mutations of ABCR have been localized within the ATP binding cassettes called NBD1 & NBD2. Very little is known regarding the energy transduction process mediated by these two domains. Dr. Biswas-Fiss is testing the hypothesis that domains NBD1 and NBD2 interact, and that this interaction influences ABCR function, in particular ATP hydrolysis. Through the use of cloning and the in-vitro expression of the two halves of the ABCR molecule as individual polypeptides, she is examining the structure and function of each half of the protein. It is hoped that these highly focused molecular/biochemical studies will facilitate better methods of disease diagnosis and treatment, as well as the ability to provide more accurate prognoses of disease development.

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Deborah Ann Ferrington, Ph.D.
University of Minnesota
Minneapolis, Minnesota
Project: Proteomics of Progressive Stages of Macular Degeneration

There is currently no preventative treatment for age-related macular degeneration (AMD), the leading cause of blindness among the elderly in the U.S. The development of therapeutic interventions will require an understanding of the molecular events associated with this disease. In this project, Dr. Ferrington is testing the hypothesis that there is a subset of proteins that are uniquely altered in patients with AMD. She also hypothesizes that the progression of AMD involves an evolution of protein changes that are manifested in clinically distinct features. Her team is working to clinically and biochemically evaluate the macular region of the neural retina and retinal pigment epithelium (RPE) from human donor eyes (from donors aged 65 to 75 years). The selected tissues will include those exhibiting no AMD, those with retinal features that indicate of the beginning of AMD, and those showing the later stages of the disease. The goals of this research are to evaluate and classify retinal degeneration in donor eyes through biochemical analysis, and to identify alterations in retinal proteins using proteomic analysis. Using donor retinas at clinically defined stages of AMD should aid in distinguishing patterns of protein changes that occur with the progression of the disease. Also, identifying changes in proteins that are uniquely altered in the disease pathology will provide valuable insights into the mechanism of the disease process, and may provide new targets for treatment.

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Paul Mitchell, M.D., Ph.D.
University of Sydney
Sydney, Australia
Project: Serum Markers for Vascular Risk in Persons with AMD

One recently identified risk factor for AMD is a history of atherosclerotic vascular diseases, such as heart attack and stroke, high blood pressure, high cholesterol levels and a high dietary fat intake. AMD may therefore represent an atherosclerotic or inflammatory vascular disease that is manifested in the eye as well as the principal sites of heart and brain. However, the level of inflammatory markers in the blood of patients with AMD compared to those without AMD is unknown. Dr. Mitchell’s hypothesis is that the pathogenesis of AMD includes vascular risk factors, and that inflammatory markers of vascular risk in the blood may also be markers for the development and progression of AMD. He is working with data obtained from a large population-based survey of vision and common eye diseases, including AMD, in an urban population in the Blue Mountains region west of Sydney, Australia. His study also includes the clinical data and stored blood samples of patients. His goal is to assess the relationship between AMD and several inflammatory blood markers, including C-reactive protein, fibrinogen, intercellular adhesion molecule-1, interleukin-6, von Willebrand factor, plasminogen-activator inhibitor-1, and plasma homocysteine. By identifying previously unknown risk factors for AMD, this work could lead to new therapeutic and preventive options for the management of the disease.

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Silke Schmidt, Ph.D.
Duke University Medical Center
Durham, North Carolina
Project: Genetic Variability in APOE and NOS Genes in AMD

A large body of evidence now points to genes as major risk factors for age-related macular degeneration (AMD). A gene known as the apolipoprotein E (APOE) gene is currently considered one of the most promising candidates. The goal of this study is to further investigate the potential role that APOE may play in AMD. This gene carries the information for producing the APOE protein, which is an important molecule for many biological processes, including the transport of cholesterol within the human body. APOE occurs in three different forms (called alleles). The APOE-4 allele is associated with an increased risk of Alzheimer’s disease and heart disease, but previous studies have suggested that the APOE-4 allele may actually reduce the risk of AMD. To explore this hypothesis, Dr. Schmidt’s team is analyzing a large AMD data set that includes data from other U.S. and European research groups to examine APOE’s effects on AMD. This work takes into consideration some recently published research suggesting that APOE alleles influence the levels of a chemical compound called nitric oxide (NO) in the eye. NO is a messenger molecule with diverse functions throughout the body. It is thought that certain NO levels may be able to prevent or delay damage to cells whose normal function is the protection and nourishment of the retina, the so-called retinal pigment epithelium (RPE). A second hypothesis being explored is the theory that genetic alterations in the genes that are directly responsible for NO production may also contribute to the risk for AMD. It is hoped that a better understanding of these genetic risk factors can lead to new treatment or prevention strategies for AMD.

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