DESCRIPTION (provided by applicant): Age related macular degeneration (AMD) is the leading cause of vision loss and blindness in individuals over age 65 in the developed world. While the cellular mechanism causing AMD remains unclear, evidence from basic research and epidemiological studies suggest that oxidative tissue injury plays a major role in the pathogenesis of the disease. In this proposal, we will test the hypothesis that the pathogenesis of AMD involves oxidative damage to proteins and lipids of the retina. By optimizing clinical tissue analysis, we will be able to establish a pattern of uniquely altered proteins that distinguishes normal aging from pathologic aging in AMD. The proposed research will take a novel approach to studying the pathogenesis of AMD by using human retinal tissue, grading this tissue according to current clinical standards, analyzing the tissue with sophisticated ophthalmoscopic imaging techniques that detect oxidative injury, and utilizing proteomic technology to define retinal subproteomes for each stage of AMD. The following aims will be pursued: (1) Link the proteomics of AMD to epidemiological and clinical studies of AMD. (2) Detect and quantify lipofuscin to assess its role in the pathologic aging of AMD. (3) Develop subproteome profiles of human retinal tissue for each category of AMD. This global survey of proteins will pinpoint cellular pathways and potential subcellular mechanisms, linked to specific clinical stages that can be attributed to the disease process. This information will enable us to generate a rational approach to identify targeted therapies.