The reaction of arachidonic acid with cyclooxygenase or lipoxygenase gives rise to prostaglandins and leukotrienes, respectively. These eicosanoids are important regulators of homeostatic and pathophysiologic processes, including inflammation and cancer. We have previously described a unique catalytic activity of the inducible isoform of cyclooxygenase, COX-2, in a reaction with the 5-lipoxygenase product, 5-hydroxy- arachidonic acid. COX-2 catalyzed oxygenation of 5-hydroxy-arachidonic acid gives rise to hemiketal (HK) eicosanoids as well as 5-hydroxy-prostaglandins (5-OH-PGs). Both groups of eicosanoids were discovered by us, the latter only very recently. We hypothesize that these novel eicosanoids act as autocrine and paracrine regulators of myeloid, lymphoid, and endothelial cell function. We will analyze the role of HKs and 5-OH-PGs in endothelial cell tubulogenesis, T cell activation and differentiation, receptor binding and activation, kinase signaling, and platelet aggregation.
In specific aim 1 we will test the hypothesis that HKs mediate endothelial cell tubulogenesis and migration through kinase signaling. We will also analyze how HKs mediate T cell activation and differentiation.
In specific aim 2 we will test the hypothesis that 5-OH-PGs bind traditional PG receptors and mediate signaling. Preliminary studies have shown that 5-OH-PGs bind at EP receptors and have an effect on platelet aggregation. To test this hypothesis we will determine the binding affinity of 5-OH- PGs at human prostanoid receptors and determine their signal transduction as agonists or antagonists.
In specific aim 3 we will analyze the effect of 5-OH-PGs on the aggregation of human platelets. Our studies will substantially expand the range of eicosanoids formed specifically by COX-2. Elucidation of the biological activities of the novel eicosanoids will help better understand the function of their biosynthetic enzymes in inflammation as well as the therapeutic effects of the drugs used to inhibit prostaglandin and leukotriene biosynthesis.
We propose to study new lipid mediators that are formed in the body in response to injury or infection. We want to determine how they change the body's response to infection, specifically, how they change the immune response and influence the clotting of platelets in the blood. Our results may help better understand the effects of common over-the-counter medications like aspirin and Tylenol that inhibit the formation of the novel lipid mediators.
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