? It is well known that prostaglandins play a key role in the pathophysiology of asthma and cancer. Prostaglandin synthesis begins with the rate-limiting step, the formation of arachidonic acid (AA), via the activity of phospholipase A2. Inflammatory cytokines, such as TNFalpha and IL-lbeta, induce the activation and translocation of cytosolic phospholipase A2 (cPLA2). However, neither the mechanism nor all the mediators involved have been elucidated. The enzyme, COX-2, utilizes AA released by cPLA2 to begin the prostaglandin synthetic pathways. Our laboratory found that the sphingolipid metabolite, ceramide-l-phosphate, is a novel mediator of cPLA2 activation and prostaglandin synthesis. Our central hypothesis is that ceramide-l-phosphate produced from the phosphorylation of ceramide by ceramide kinase is an important mediator of prostaglandin synthesis through the direct activation of cPLA2 in response to inflammatory cytokines. To validate our hypothesis, we propose: 1) To determine the physiological regulation of the formation of ceramide phosphate in response to inflammatory cytokines; 2) To determine the role of ceramide kinase in regulating prostaglandin synthesis in response to inflammatory cytokines; and 3) To determine the role of ceramide-l-phosphate in the direct mechanism of cPLA2 activation in response to inflammatory cytokines. This work will define key mechanisms regulating the production ceramide-l-phosphate and define the role of ceramide-l-phosphate in mediating prostaglandin synthesis. The results should generate significant insight into novel aspects of signal transduction by lipids, regulation of ceramide kinase and cPLA2, and the regulation of prostaglandin synthesis which might lead to new therapeutics in thrombosis, cancer metastasis, inflammation, and asthma. ? ?
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