The overall goal of the proposed studies is to understand the mechanisms involved in ischemic cell injury and repair of tissue post-ischemia. The current proposal will focus on: 1) the role of phospholipase A2 (PLA2) in the injury process; and 2) molecular events regulating tissue repair. The first Specific Aim of the application is to purify and further characterize a Ca2+-independent form of PLA2 in the kidney and to determine the contribution to injury of this form of PLA2, as well as the cytosolic 100-110 kD PLA2 (cPLA2) which we have purified. The Ca2+- independent form of PLA2 will be purified from the kidney, its substrate specificity characterized, antibodies to the protein made, and its cDNA cloned. Potential changes in enzymatic activity with ischemia will be evaluated. Possible mechanisms of activation of PLA2, in particular cPLA2, in ischemia/reperfusion will be examined. These possible regulatory mechanisms include: translocation of the enzyme to the membrane, changes in levels of PLA2 activating protein (PLAP), and post- translational modifications of the enzyme such as phosphorylation. Cell lines will be established, which overexpress normal or altered cPLA2 or suppress expression of cPLA2, and these lines will be used to establish mechanisms of regulation of cPLA2 and contribution of cPLA2 to cellular injury associated with the energy depleted state. The second Specific Aim is to characterize a novel kidney-specific zinc finger putative transcription factor, Kid-1, which we have cloned, whose expression is regulated in renal ontogeny and by ischemia/reperfusion, or folic acid administration. The Kid-1 protein will be expressed, antibodies raised to it and the intrarenal expression of Kid-1 localized and correlated with immunohistochemical localization of markers of differentiation and mitotic activity. The effect of Kid-1 expression on cell proliferation, and early response gene expression will be evaluated. The cDNA will be transfected into kidney cells and fibroblasts, and effects of expression on cell cycle progression and on immediate-early gene expression will be evaluated. The genomic structure of Kid-1 in the rat and mouse, including potential 5' regulatory domains will be mapped. Since this gene is expressed predominantly in the kidney it is possible that a promoter or enhancer has characteristics that confer kidney specificity. These experiments will provide insight and reagents which can be used to understand the role of PLA2 and Kid-1 in physiological as well as pathophysiological processes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Pathology A Study Section (PTHA)
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Massachusetts General Hospital
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