The long-term goal of this research project is to provide new molecular information about components and reactions of the visual cycle and about the control of retinoic acid biosynthesis in retina. During daylight, a continual rain of photons bleaches visual pigments in photoreceptor cells of our retinas to initiate phototransduction. Simultaneously reactions of the visual cycle in RPE replenish the bleached chromophore and provide for continual regeneration of visual pigments. Vision requires a balance between these two processes to establish a new steady level of bleached visual pigment at each different level of illumination. While phototransduction has been well studied, we know relatively little in a molecular sense of the components or control of the visual cycle. During the course of this project a detailed investigation of the enzymology and chemistry of visual cycle reactions will be carried out. Particular emphasis will be placed on determining the factors that control levels of all-trans-retinaldehyde in the photoreceptor cell, on determining the role of retinoid-binding proteins in cycle activity and on obtaining structural information about one of the enzymes of the cycle. Retinoic acid and its carrier protein CRABP are present in retina in relatively large amounts. Since this retinoid cannot be reduced to retinaldehyde or retinol in vivo, and thus cannot participate n the visual cycle, it is likely to be involved in other aspects of vitamin A function. The question of retinoic acid function in retina will be addressed, concentrating on providing a molecular description of the enzymes and control involved in its synthesis. An understanding of the underlying causes of clinical retinal disease requires an appreciation of the fundamental processes that produce the visual response. At present, the relative paucity of detailed information about visual cycle enzymes and their control and retinoic acid function and biosynthesis in retina, precludes even asking relevant questions about possible relationships to retinal disease. The concepts, structural information, antibodies, and cDNA probes that will be obtained during this project period will allow future exploration of the relationship of retinoid metabolism to retinal disease.
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