The objective of the proposed research is to utilize Drosophila as a model for studying hereditary human diseases that cause retinal degeneration and eventual blindness [retinitis pigmentosa (RP) and age-related macular degeneration (AMD)]. The complexity and variations of human RP and AMD suggest that there are multiple subtypes of the diseases, each with distinct genetic and biochemical bases. This complexity, the infrequent availability of ocular tissues from RP and AMD patients, and the broad base of knowledge of Drosophila molecular genetics, combine to make Drosophila a powerful animal model for studying inherited retinal degeneration disorders. We propose to use an integrated strategy of biochemical, cell biological, electrophysiological, genetic, and molecular approaches to identify and characterize mutations that cause defects in protein transport and targeting. We have identified three mutant lines of flies that display secretory pathway defects and retinal pathology. We will identify the corresponding genes and subject them to a detailed genetic and molecular analysis. In addition, we will continue to screen 12,000 individual mutant lines for retinal degeneration. The screen is based on a simple morphological phenotype that may be screened in live flies under the dissecting microscope. Mutants that define constituents of the secretory pathway and protein targeting will be subjected to a detailed characterization. Our findings will be utilized to screen a highly defined set of human AMD and RP patients for similar defects. Genetic analysis in Drosophila remains a powerful means of rapidly identifying genes that are essential for protein trafficking and normal photoreceptor function. It is anticipated that genes identified in this study will provide insights for the genetics of AMD and RP in humans.
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