Our goal is to investigate the biochemistry and physiological significance of the arachidonic acid cascade, particularly the lipoxygenase-leukotriene pathway, and the inositol lipid cycle in the retina. The focus is on visual cell - pigment epithelium interactions during photoreceptor renewal. In other systems, metabolites arising from receptor-stimulated turnover of phosphoinositides and from the arachidonic acid cascade are potent mediators of intracellular and intercellular signals. The proposed experiments will: 1) correlate changes in arachidonic acid metabolism in rod outer segments and pigment epithelium with particular stages (times) of photoreceptor shedding; 2) study the effect of inhibitors of leukotriene and prostaglandin synthesis on photoreceptor disk shedding in an eyecup preparation; 3) investigate the involvement of inositol polyphosphates and the inositol lipid cycle as a transmembrane signaling system for modulation of shedding and/or phagocytosis; and 4) characterize the involvement of the arachidonic acid cascade and inositol lipids in the modulation of phagocytosis in pigment epithelium cells in culture. Powerful analytical procedures, such as high performance liquid chromatography, capillary and open column gas-liquid chromatography, gas chromatography-mass spectrometry and radioimmunoassay, will be used to examine biochemical changes and to establish correlates with a histological assessment of disk shedding and phagocytosis. The results obtained will define the involvement of the arachidonic acid cascade and the inositol lipid cycle in the modulation of the interactions between visual cells and retinal pigment epithelium.
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