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FUNDING PERIOD: APRIL 1, 2004 - MARCH 31, 2006 Jayakrishna Ambati, M.D. Lynn K. Gordon, M.D., Ph.D. Stephanie Hagstrom, Ph.D. Elizabeth J. Johnson, Ph.D. Catherine Bowes Rickman, Ph.D. Steven A. Rosenzweig, Ph.D. Kumar Sambamurti, Ph.D. Deborah L. Stenkamp, Ph.D. |
FUNDING PERIOD: APRIL 1, 2004 - MARCH 31, 2006
Jayakrishna Ambati, M.D.
University of Kentucky
Lexington, KY
Project: Adeno-associated Viral Gene Therapy in a Novel Mouse Model of AMD
Progress in understanding how AMD develops and the process of developing new drug treatments has been hampered by the absence of good animal models. However, Dr. Ambati’s past research has shown that mice with a deletion of their Ccl-2 gene develop a form of ocular pathology similar to human AMD as they age. The development of early (dry) AMD as well as late (wet) AMD in these mice makes this model particularly attractive for scientists investigating the development of the disease and the mechanisms that mediate the progression of dry AMD to the more severe wet form. Dr. Ambati’s goal is to replace the function of the deleted Ccl-2 gene in these mice using an adeno-associated virus (AAV) as a vector. By treating one eye with active AAV therapy (which will deliver the Ccl-2 gene) and treating the other eye with a control AAV treatment, Dr. Ambati hopes to gain a better understanding of the molecular mechanisms underlying the development of AMD. These studies could also provide definitive proof that the absence of the Ccl-2 gene is directly responsible for the development of AMD in mice, and will justify an investigation of potential mutations in the Ccl-2 gene in humans with AMD. This in turn could lead to the identification of new therapeutic strategies to prevent blindness and restore sight.
Lynn K. Gordon, M.D., Ph.D.
University of California
Los Angeles, CA
Project: Role of EMP2 in Homeostasis
Complex interactions between a key cell type, the retinal pigment epithelium (RPE) and the underlying extracellular matrix may play a critical role in the pathophysiology of age-related macular degeneration (AMD) as well as in proliferative vitreoretinopathy (PVR). Dr. Gordon has observed that RPE express epithelial membrane protein (EMP2), a protein that may play a significant role in the recruitment and targeted cell surface delivery of certain proteins to specific regions of the cell membrane. The purpose of this study is to test whether the modulation of EMP2 expression in the RPE produces the predicted biologic consequences, including altered growth characteristics and changes in patterns of cellular adhesion and migration. The expected improvement in the understanding of the biochemical pathways and the regulation of the various functions performed by the RPE could yield important insight into the pathophysiology of age-related macular degeneration, PVR, and hereditary retinal degenerations. It could also lead to the identification of new targets for the treatment of RPE-associated pathology.
Stephanie Hagstrom, Ph.D.
Cleveland Clinic Cole Eye Institute
Cleveland, OH
Project: Genomic and Proteomic Markers of AMD Susceptibility
Slowing or preventing the progression of age-related macular degeneration (AMD)
has become an important U.S. public health goal. Dr. Hagstrom is testing
the hypothesis that biomarkers of AMD susceptibility exist in the blood.
Physicians could use such a test for initiating preventive interventions
to slow the progression of the disease and to monitor the effectiveness of
therapies used to lower biomarker levels. A blood test would also allow physicians
to alert those at risk to possible AMD risk factors (such as smoking, diet
and sun exposure) and prescribe appropriate lifestyle modifications. The
goal of this research is to identify genomic and proteomic markers of AMD
susceptibility in a subset of the genes that have been identified as components
of drusen that has been isolated from eyes with AMD. Dr. Hagstrom will also
study the effects of oxidative protein modifications in the plasma from donors
with AMD. The results of these studies could help scientists identify patient
risk factors and design appropriate interventions to reduce them.
Elizabeth J. Johnson, Ph.D.
Tufts University
Boston, MA
Project: Antioxidant Status and Risk of Age-Related Maculopathy
Oxidative stress is high in the eye due to the lifelong exposure to light and the high rate of oxidative metabolism in the retina. Researchers believe that cumulative oxidative damage may play a role in the pathogenesis of age-related maculopathy (ARM). Lutein and zeaxanthin are carotenoids (plant pigments) that selectively accumulate in the macula part of the retina, where they become major components of macular pigment. Lutein and zeaxanthin are also known to function as antioxidants, and may protect the macula from light-initiated oxidative damage. In this study, Dr. Johnson is measuring the retina’s antioxidant capacity in relation to individual carotenoids, including lutein and zeaxanthin, and the markers of inflammation. This data will then be evaluated in relation to existing data on macular pigment, body mass index and the presence of ARM in patients. It is hoped that the measurement of antioxidant capacity and carotenoid status will prove useful in assessing the risk of ARM and in increasing our understanding of ARM pathophysiology.
Catherine Bowes Rickman, Ph.D.
Duke University Medical Center
Durham, NC
Project: A Murine Model of AMD with CNV and Sub-RPE Deposits
A gene that has been implicated as a risk factor in age-related macular degeneration (AMD) is apolipoprotein E, or apoE. The human apoE gene exists in three variations or alleles, designated as apoE2, -E3 and -E4. Dr. Bowes-Rickman is studying the relative roles of each form of apoE, along with aging and diet, on the structural integrity of the retina and its adjacent blood supply in a potential mouse model of AMD. She has hypothesized that the combination of three major risk factors for AMD―apoE isoform expression, aging and diet―cause pathological changes in the retina, including the formation and accumulation of debris under the retinal pigmented epithelium (RPE) and new blood vessel growth. Her goal is to produce a mouse model that closely approximates these features of human AMD. This murine model can then be induced to express the defining events that lead to choroidal neovascularization in late AMD and provide a model for testing new therapies.
Steven A. Rosenzweig, Ph.D.
Medical University of South Carolina
Charleston, SC
Project: Pathways Regulating Angiogenesis in Epithelial Cells
Bruch’s membrane is a layer of retinal tissue upon which the retinal pigment epithelium (RPE) lies. Just below Bruch’s membrane is the choroid layer, a region containing many blood vessels and capillaries. The increased growth of new capillaries in the choroid layer (as seen in wet macular degeneration) is initiated through the action of growth factors on endothelial cells, which are the building blocks of capillaries. Vascular endothelial growth factor (VEGF) has been identified as the principal agent responsible for new capillary growth (angiogenesis) in the body. But it is also known that other growth factors can participate in the progression of ocular neovascularization. These factors have been identified as bFGF, TGFß, PDGF and IGF-1. So far, there is little information on the role that IGF-1 plays in neovascularization, but Dr. Rosenzweig has shown that IGF-1 stimulates the secretion of VEGF by RPE cells in culture. He is now studying how VEGF secretion is regulated in human RPE cells in tissue culture by treating them with IGF-1 or hypoxic conditions. This study could lead to the identification of new drug targets for the inhibition of choroidal neovascularization in age- related macular degeneration..
Kumar Sambamurti, Ph.D.
Medical University of South Carolina
Charleston, SC
Project: Role of Alzheimer’s APP in Retinal Degeneration
Recent studies have made an exciting connection between Alzheimer’s disease (AD) and age-related macular degeneration (AMD) by identifying amyloid beta protein (Aß) deposits in drusen and showing that retinal cells are very sensitive to Aß toxicity. These studies suggest that Aß could play an important role in the pathogenesis of age-related macular degeneration. Dr. Sambamurti is working to create a mouse model that overproduces Aß in the brain as well as in the retina in order to shed light on some of the pathology associated with age-related macular degeneration. His goal is to use this model to understand the effects of Aß on retinal function in general and on drusen formation in particular. He also hopes to identify risk factors for retinal degeneration and to evaluate the effects of known drug agents that might inhibit the biogenesis of Aß in the retina.
Deborah L. Stenkamp, Ph.D.
University of Idaho
Moscow, ID
Project: A Genetic Model for Age-Related Cone Degeneration
Age-related macular degeneration (AMD) is a progressive disease that causes severe visual impairment. This disease affects retinal pigmented epithelium (RPE) cells and photoreceptor (light-sensitive) cells, resulting in a loss of visual function. In her previous research, Dr. Stenkamp observed that cone photoreceptors degenerate in aging zebrafish that carry a deletion allele (or variation) for a known gene. This gene encodes a signaling protein that is secreted by the RPE that supports the development of new photoreceptors. This data suggests that the genetic variation for this deletion may provide a model for age-related photoreceptor degeneration. Dr. Stenkamp’s goal is to use this model to gain a better understanding of age-related photoreceptor loss, to identify underlying genetic causes of AMD, and in the future, to test new therapies for age-related macular degeneration.