Matrix metalloproteinases are enzymes which are important in skin wound repair and remodelling and inflammation. the mechanisms through which eicosanoids regulate the expression of these enzymes will be examined. Key events in the eicosanoid regulation of the matrix metalloproteinases interstitial collagenase, stromelysin, and their inhibitor TIMP will be documented. The transcriptional factors through which eicosanoids regulate gene expression will then be examined in this well-defined system, to elucidate the physiologic regulatory pathways through which eicosanoids activate cellular transcription. These events will be correlated with measurements of signal transduction events such as Ca++ flux, diacylglycerol formation and phosphotidylinositol release. The structural chemistry of the lipids which regulate expression will then be defined in essential fatty acid deficient rumor cell lines. Collectively, these studies will form the rational basis for design of lipid analogue inhibitors and agonists of metalloproteinase synthesis. The expertise and assistance of Drs. Stenson and Morrison will be utilized in conducting these signal transduction and structure- function studies. Many of their established assays will be used, as well as making extensive use of the analytical core mass-spectroscopy and fluorometry facilities.
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