The proposed program project is directed towards understanding mechanisms of eicosanoid synthesis, function and regulation in both physiologic and pathologic states. Research proposal #1 focuses on the biochemical and cellular mechanisms, regulation and manipulation of the changes that occur in ureteral obstruction and renal infarction including the exaggerated arachidonate metabolism, inflammation and altered renal function. Project #2 uses essential fatty acid deficiency to examine the role of eicosanoids in initiating and perpetuating the inflammation and functional deficits of immune-mediated glomerulonephritis. Project #3 examines the synthesis, regulation and function of eicosanoids in normal epidermis and in skin injury and repair. Project #4 focuses on the identification and biochemical significance of eicosanoids and phosphoinositide hydrolysis products in pancreatic islet cell function. Project #5 deals with the role of eicosanoids and the phosphoinositide metabolites in the molecular mechanisms of volatile anesthetics/convulsants. Project #6 focuses on how physiological agonists stimulate eicosanoid production, phosphoinositide hydrolysis, changes in intracellular Ca++ and electrolyte transport in homogeneous populations of cultured renal cells. The program project is dependent on extensive interactions between investigators, particularly with respect to a) the identification of eicosanoids using gas chromatography/mass spectrometry (Core A), b) the understanding of the biochemistry of the phosphoinositide cycle, c) the manipulation of eicosanoid metabolism using essential fatty acid deficiency, and d) the cellular mechanisms of enhanced arachidonate metabolism in tissue injury. The goal of the proposal is the beneficial manipulation of eicosanoids and inositides in physiologic (renal and islet cell function), pharmacologic (anesthetic/convulsant action), and pathologic (renal injury, postobstructive diuresis, glomerulonephritis, psoriasis, diabetes) states.
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