Acquisition of the capacity of mammalian sperm to fertilize ova is achieved during passage through the epididymis. Over the last two decades several dozen androgen-dependent features related to the function of the epididymis have been described. Our research for the past thirteen years has been directed toward achieving a molecular understanding of these events. The focus of the research was changed in the last three years from its previous orientation (a study of changes in sperm) to a study of the metabolism of the epididymal epithelial cell, since it now appears that most (if not all) changes in sperm are driven by the ever changing nature of the epididymal luminal environment. Our most recent results have pinpointed one type of lipid metabolism, specifically metabolism of arachidonic acid to ecosinoids (20 carbon compounds including prostaglandins and leukotrienes) as a possible dominant feature in the regulation of epididymal cells. The specific objective for this project period is to test an original hypothesis offered to explain how such a wide spectrum of functions could be regulated by one feature, change in androgen status. A model is provided in this proposal and serves as the focal point for the ultimate interpretation and integration of the multitude of separate observations made by others. Specifically, I propose that androgen status regulates the key enzyme(s) related to release of arachidonyl residues from phospholipids supplied via lipoproteins (certainly phospholipase A2 and perhaps phospholipase C are involved). Tissue and cellular specific metabolism converts the released acyl reside to a family of ecosinoid metabolites. These metabolites, operating by mechanisms similar to those described for them in other tissues (kidney, intestine, pulmonary tract), direct the functions of the various regions of the epididymis [one initiation mechanism + cellular specific formation of a spectrum of metabolites = organ function]. A series of projects, ranging from whole animal endocrinology and analysis, to characterization of the metabolic potential of cultured cells, to the effect of ecosinoids on cell function are outlined to provide a direct test of this hypothesis.
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