Retinitis Pigmentosa (RP) defines a broad group of inherited retinal disorders characterized by the degeneration of rod and cone photoreceptors. A salient feature of photoreceptors is the presence of an elaborate membrane structure that houses opsin and associated phototransduction machinery required for light detection, the membrane discs of the outer-segment (OS) in vertebrates and the rhabdomeres of invertebrates. With respect to RP, many of the diseased loci are critical for the creation and maintenance of OS, the light gathering organelle. Thus our challenge is that if any advancement is going to be made toward effective therapeutic intervention with regards to mutations that perturb OS biogenesis a coherent understanding of the normal cellular mechanisms for biogenesis is essential. To date the molecular and cellular mechanisms required for OS formation are undefined and competing models exist. This proposal will focus on the biology of Prominin to further our knowledge of outer-segment membrane disc morphogenesis. Prominin localizes to the newly formed nascent discs. Directed murine knock-out of Prominin1, analyses of several inherited human retinopathies, and Drosophila prominin mutants have all demonstrated an essential role for Prominin in generating and maintaining the integrity of the photoreceptor light gathering organelles. In this proposal we combine the technological advances of proteomics and genetic in vivo capacity of Drosophila to explore numerous unanswered facets of Prominin biology required for disc membrane morphogenesis and photoreceptor integrity. The discovery of these pathways will contribute to our understanding of the cellular functions required for OS membrane disc morphogenesis, the molecular mechanisms of Prominin induced retinal degeneration, and reveal potential avenues for therapeutic intervention.
A salient feature of photoreceptors is the presence of an elaborate membrane structure, the outer-segment, which houses the millions of proteins required for light detection. Frequently, retinal diseases are characterized by the degeneration of this structure. Thus our challenge is that if any advancement is going to be made toward effective therapeutic intervention with regards to mutations that perturb the outer-segment a coherent understanding of the normal cellular mechanisms for outer-segment biogenesis is essential.
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