The objective of the proposed studies is to test the hypothesis that the process of drusen formation is stimulated by complement-mediated inflammatory events involving retinal pigmented epithelial (RPE) cells. Drusen are extracellular deposits that form between the RPE and Bruch's membrane, and are a significant risk factor for age-related macular degeneration (AMD). In AMD, functional compromise and ultimately death of RPE cells as a consequence of drusen formation is thought to lead to secondary degeneration of retinal photoreceptor cells and visual loss. Studies of age-related human diseases that, like AMD, involve cellular degeneration and the formation of insoluble deposits (e.g., Alzheimer's disease, atherosclerosis and kidney glomerulonephritis) now implicate complement activation and inflammatory events as key elements in disease processes. Data that we generated during the prior application period strongly suggest that complement activation also plays an important role in the formation of ocular drusen. We observed that terminal complement complexes and complement regulatory molecules are present in drusen, as are molecules with potential complement-activating properties. Furthermore, our observations show that RPE cells overlying drusen exhibit a compromised molecular phenotype that is consistent with a well-characterized cellular response to complement attack. Thus, these observations suggest an AMD disease process that is consistent with that of other age-related human diseases. A process that involves a primary pathogenic or age-related stimulus, the effects of which are exacerbated by localized, self-perpetuating, complement-mediated tissue destruction and inflammatory sequelae that persist over decades. The studies proposed here will examine the hypothesis that complement-mediated events contribute both to the process of drusen formation, and to the functional compromise of drusen-associated RPE cells. The studies will target the following specific aims: (1) To determine if RPE cell compromise is the result of complement-mediated attack, (2) To characterize the nature of the complement-mediated processes involved in drusen formation, and (3) To examine RPE cell responses to complement attack utilizing an in vitro model system.
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