During the past decade the accomplishments of our research effort have established the liver as a novel and important model in which to characterize the autocrine and paracrine mediator response of platelet- activating factor. Our experiments have provided insights into the nature and regulatory characteristics of the PAF receptor and have provided at least a glimpse of the importance of PAF as a mediator of hepatic responses to systemic and localized hepatic pathophysiology. PAF is synthesized in Acting through specific receptors and well defined signal transduction mechanisms, activation of glycogenolysis and glucose output. Temporally later in a trauma-response view, represents a key factor in regulating the entry of inflammatory cells from the circulation into the compromised liver. In the next grant period we will pursue four major experimental issues designed to characterize: 1) the regulation of two key of PAF receptor mRNA synthesis, and 4) the role of PAF as an inflammatory mediator in three relevant models of hepatic injury, e.g., ischemia/reperfusion, bile duct ligation-induced jaundice and sepsis/endotoxemia. In each of these hepatic injury models we have measured an increase in the hepatic PAF content and we need to understand the consequences of this finding which impinge upon the hemodynamic and metabolic functions of the liver. Our efforts will be aided greatly by several novel reagents developed during the past grant period, the most important of which are specific anti-PAF receptor antibodies to be employed in studies of the regulatory mechanisms of the proposed study will be the solubilization, stabilization and purification of the acety1CoA::lysoPAF acetyltransferase which most probably is the key regulatory step in PAF synthesis in macrophage-type cells. Successful outcomes from our proposed experiments will make a significant contribution to our knowledge-based concerning the inter- and intracellular signaling mechanisms operative in the mammalian liver as its responds to pathophysiological episodes.
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