The renewal of this program project is directed towards a continuation of an understanding of the mechanisms of eicosanoid synthesis, function and regulation in both physiologic and pathological states. Dr. Alice Pentland will attempt to determine the transcriptional factors through which eicosanoids regulate gene expression for matrix metalloproteinases, collagenase, stromelysin and their inhibitor TIMP. She will attempt to correlate the regulation of the genes for these various matrix proteins will measurements of signal transduction events such as calcium flux, diacylglycerol formation and phosphatidyl inositol metabolism. The structural chemistry of the lipids which regulate expression will then be defined in an essential fatty acid deficient tumor cell line. Dr. Holtzman's aims are to define the fatty acid oxygenation pathways expressed in human keratinocytes using analytical lipid chemistry, protein chemistry, immunochemistry and molecular biology in freshly isolated and cultured epidermal cells and in epidermal tissue. He will then seek to determine the mechanisms for the regulation of the proposed keratinocyte arachidonic 12 mono-oxygenase and cyclooxygenase (PGG-H synthetase) using the same techniques in freshly isolated and cultured epithelial cells and epidermal tissue.
His specific aims will involve collaborative interactions with Drs. Pentland, Morrison and Stenson. Dr. Morrison will explore in this proposal the role of lymphokines in particular interleukin-1 and tumor necrosis factor alpha by themselves and/or in synchrony with the growth factors PDGF, TGFbeta and EGF on the biochemical events leading to changes in function or expression of eicosanoid in the glomeruli mesangial cells. These experiments have certain elements in common with the proposal of Dr. Pentland and Dr. Morrison and Dr. Pentland will have a close interaction through all phases of the specific aims.
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