ROLE OF DOCOSAHEXAENOIC ACID METABOLISM IN RETINA

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The metabolism and physiological significance of docosahexaenoic acid, a major fatty acid of photoreceptors, remain largely unknown. The present proposal is a continuation of our ongoing studies focusing on several aspects of the cell biology of docosahexaenoic acid metabolism. The hypothesis to be tested is that the supply, uptake and metabolism of docosahexaenoic acid in the visual cell plays a central role in the development, renewal and function of photoreceptor membranes. The proposal follows a postnatal developmental approach to study docosahexaenoic acid metabolism in dissociated rod photoreceptor cells prior, during and after outer segment biogenesis in normal mice and in mice with retinal degeneration. Since docosahexaenoic acid is derived from linolenic acid, an essential fatty acid supplied by the diet, the origin of retinal docosahexaenoic acid, its synthesis from linolenic acid in the liver and its transport via the blood to the retina, will be studied. Another goal of this proposal is to correlate docosahexaenoic acid metabolism with photoreceptor shedding and phagocytosis in the frog. The retina synthesizes docosanoids (22-carbon, leukotriene- like compounds). This proposal will test the hypothesis that these metabolites are involved in signaling mechanisms involved in photoreceptor shedding. Docosanoids formed in response to shedding and the enzymes responsible for docosanoid production will be characterized. The possibility that the docosanoid-producing enzymes are distinct from lipoxygenases involved in arachidonic acid metabolism will be explored. In addition, the subcellular localization of docosanold production will be determined. The approach proposed for these studies combines cell biological techniques (dissociated rod photoreceptor cells, autoradiography and eye cup preparations) with highly sensitive and specific biochemical procedures (high-performance liquid chromatography, capillary gas-liquid chromatography, gas chromatography-mass spectrometry) and should contribute to a better understanding of the role of docosahexaenoic acid in visual cells.