Research in the Pharmacological Sciences Center addresses the biosynthesis, metabolism, function and pharmacology of eicosanoids and related biologically active compounds. The scientists in this Center include clinical pharmacologists and other clinical investigators working in close association with molecular pharmacologists as well as analytical and organic chemists. Research by Center investigators has provided completely new insights into the pharmacology of niacin, the effective use of which in the treatment of hyperlipidemia is limited substantially by adverse effects. The hypothesis that tissue macrophages are the sources of niacin-induced eicosanoid release will be explored. The molecular basis for the exquisite sensitivity of the release of PGD2 by niacin to very low doses of aspirin will be investigated, together with the regulation by prednisone of the cellular capacity for niacin-induced eicosanoid biosynthesis. The mechanism whereby niacin engenders this cellular response will also be addressed. Investigation of the mechanisms of oxygenation of arachidonic acid will examine the P450- dependent synthesis of hydroxyeicosatetraenoic acids, and will address the relationship of structure to the function of lipoxygenases with stereospecificity for synthesis of lipoxygenase products with the """"""""R"""""""" configuration. Building on the characterization of the gene for the 5- lipoxygenase enzyme, the biological function of 5-lipoxygenase products will be addressed through efforts to achieve inactivation of this gene in the mouse through the approach of the homologous recombination. The induction of asthma and the syndrome of systemic mast cell activation by aspirin in some patients strongly implicates eicosanoids in the pathophysiology of these two clinical disorders. Findings that implicate PGE2 as a restraint on the cellular events leading to aspirin-evoked systemic mast cell activation provide a basis for the proposed research to further investigate its participation in the regulation of the syndrome of systemic mast cell activation, including idiopathic anaphylaxis, and for the examination of a therapeutic hypothesis. The mechanism of aspirin-evoked asthma will be investigated in studies that examine the cellular basis for this phenomenon as well as the possible participation of prostaglandin E2 in modulating the pathophysiology of the airway in this and related conditions. This research is conducted in coordination with an analytical core that provides support in the elucidation of the structure of eicosanoids and related lipids and in the quantification of eicosanoids and their metabolites.
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