The studies of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase, now established as a major pathway for the bioactivation of endogenous AA, uncovered new and important functional roles for this enzyme system in cell and organ physiology. The most extensively characterized of the P450-derived metabolites, the epoxy- and the omega/omega-1 hydroxy-arachidonic acid, have been implicated in the regulation of tubular sodium and water transport, renal hemodynamics, and renovascular reactivity. Furthermore, associations between genetically controlled alterations in P450 function and/or expression, and the control of systemic blood pressures suggest important roles for these enzymes in kidney and body homeostasis, and in the pathophysiology of hypertension. However, the physiological significance of renal P450 and the site and mode of action of its metabolites remains to be unequivocally defined, and there is a need for advanced experimental models of P450 AA Monooxygenase, isoform-dependent, functional phenotypes. Project 2, in conjunction with the cell and organ physiology components of this Program Project, proposes to utilize molecular approaches for the development and bio-molecular characterization of models of P450 isoform-dependent function and/or dysfunction. P450 gene disruption and/or overexpression will be employed for the integrated functional and biochemical analysis of the significance and the functional role(s) of specific kidney AA epoxygenase and omega/omega-1 hydroxylases. We will apply a combination of analytical, biochemical, and recombinant DNA techniques to the analysis of P450 gene-dependent changes in eicosanoid biosynthesis, AA metabolism, and P450 isoform organ expression and regulation. The long term goals of this project are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answers to these important questions are needed for the development of meaningful approaches to the unequivocal definition of: a) their physiological significance, b) relevance to the human diseases such as hypertension, and for the development of rational strategies for future pharmacological and/or clinical intervention.
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