CONTROL OF ARACHIDONIC ACID METABOLISM IN THYMIC EPITHELIAL CELLS

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The arachidonic acid metabolites play an important role in the development of thymocytes. The levels of prostaglandins in the thymus is 4 to 10 times higher than the plasma levels. The constitutive production and the maintenance of prostaglandin levels in the thymus is probably important for the apoptosis of thymocytes resulting from the negative selection processes. The thymic epithelial cells are responsible for the production of prostagladins in the thymus. From our recent work, we have found that the production of prostaglandins by the thymic epithelial cells is regulated by PLA2 which is activated by both TGF-alpha and yet unidentified ligand that stimulates via G protein mediated pathway. In this application we propose to firmly establish the physiological role of EGF/TGF-alpha in the regulation of arachidonic acid metabolism in the thymus and identify the natural ligand that stimulate PLA2 activity through the activation of G protein. We will also elucidate the overall regulatory mechanism of arachidonic acid metabolism and identify the defective element(s) that is involved in the development of systemic lupus erythematosus (SLE) in mice. Both in vitro and in vivo studies are proposed using normal and lupus prone NZB and NZB/W mice. We will achieve our goal using both molecular biological and lipid biochemical techniques in proposed experiments.