The goal of the proposed research is to more fully exploit the fruitfly, Drosophila melanogaster, as an animal model for retinal degeneration. The Drosophila visual system has proven to be a very powerful genetic model to identify genes required for phototransduction and for photoreceptor cell survival. Over the last funding period, we set out to increase the pace of gene discovery by combining a comprehensive microarray analysis for eye-enriched genes with new large-scale screens for mutations that cause defects in visual transduction. It now appears that most of the genes essential for phototransduction are in hand. Mutations in virtually all of these result in retinal degeneration. The goal of the research proposed here focuses on this medically important phenomenon. We propose to develop additional fly models for retinal degeneration, with a new emphasis on those genes that function in processes other than phototransduction. This is an important transition in our research, since the genes that cause retinal dystrophies in humans are not restricted to those that contribute to phototransduction, but function in many additional processes, such as protein transport, cytoskeletal function, lysosomal function and sphingolipid metabolism. Moreover, many of the retinal degeneration diseases are syndromic and cause clinical manifestations outside the visual system. Multiple retinal diseases also result from defects in the production and regeneration of the chromophore in the retinal pigment epithelium. Currently, flies have not been exploited as an animal model for diseases originating in the retinal pigment epithelium or for syndromic diseases. The four specific aims of the current research are to fill these voids by developing new retinal degeneration models in Drosophila. Moreover, based on our preliminary results, we propose that studying seemingly diverse models for retinal degeneration in parallel will promote the discovery of common underlying mechanisms, raising the possibility of identifying common therapies. To accomplish our goals, we propose to employ a multidisciplinary approach using a combination of genetic, cell biological, germline transformation, electrophysiological, biochemical and microarray techniques, which we have employed over the past 19 years to dissect the molecular mechanisms of phototransduction.