The Research Center for Pharmacology and Drug Toxicology: Novel Mechanisms and Pharmacological Consequences of Polyunsaturated Fatty Acid Oxygenation brings together a tightly-knit group of experienced investigators with a shared interest in polyunsaturated fatty acid oxygenation to undertake research focused on the pharmacology, biochemistry, and biology of eicosanoids and related compounds. The goal of this research is to identify new targets for the development of therapies to modulate the formation, metabolism, and biological activities of eicosanoids and related compounds in humans. Studies suggest that oxygenated polyunsaturated fatty acid species play an important role in human physiology and pathophysiology. Thus, pharmacological manipulation of the formation of oxidized species of fatty acids provides the opportunity to prevent or treat pathophysiological processes associated with these compounds. Nonetheless, a thorough understanding, at the molecular level, of factors influencing the formation and actions of eicosanoids and related compounds remains elusive. This Center comprises five research projects and two cores that will provide important insights into the role of oxygenated species of polyunsaturated fatty acids, derived either enzymatically or non-enzymatically, in human physiology and pathophysiology. A strength of our research program is that proposed projects integrate basic pharmacological, biochemical and molecular biological approaches with translational studies involving humans. Project 1 will define biochemical pathways involved in the formation of novel glyceryl-prostaglandins (PGs) from 2-arachidonylglycerol, examine their generation in cells and tissues, and characterize their metabolism in vivo. Project 2 will test the hypothesis that PGD2 receptors are critical modulators of inflammation in the central nervous system using a variety of in vitro and in vivo models. Project 3 builds on findings that acetaminophen inhibits heme protein-catalyzed lipid peroxidation and will determine the molecular basis for this effect. In addition, studies will evaluate the inhibition of lipid peroxidation by acetaminophen-based regimens in humans with subarachnoid hemorrhage. 4-hydroxynonenal is a bioactive lipid derived from the fragmentation of peroxidized polyunsaturated fatty acids that mediates adverse effects of oxidant stress. Project 4 will focus on mechanisms by which this compound is formed in vivo and characterize novel HNE adducts. Project 5 will test the hypothesis that the oxidation of docosahexaenoic can be precisely defined in humans and leads to the formation of here-to-fore undescribed, biologically active, products containing complex cyclic structures. These studies will utilize DNA esterified in phosphatidylethanolamine, a biologically relevant form of this fatty acid. The investigators included in this research proposal are highly integrated both scientifically and intellectually and are extremely experienced in a number of facets of research related to the oxygenation of arachidonate and other polyunsaturated fatty acids. It is anticipated that the projects proposed will significantly advance our understanding of the pharmacology and biology of eicosanoids and related compounds.
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