Research Center for Pharmacology and Drug Toxicology: Novel Mechanisms and Pharmacological Consequences of Arachidonate Oxygenation brings together a tightly-knit group of experienced investigators with a shared interest in arachidonic acid oxygenation to undertake research focused on the pharmacology, biochemistry, and biology of eicosanoids. The goal of this research is to identify new targets for the development of therapies to modulate the formation of eicosanoids in humans. Epidemiological and clinical studies suggest that oxygenated arachidonic acid species (eicosanoids) play an important role in human physiology and in diseases such as atherosclerosis, cancer and neurodegenerative diseases, among others. Thus, pharmacological manipulation of the formation of oxidized arachidonate species provides the opportunity to prevent or treat pathophysiological processes associated with these compounds. Nonetheless, a thorough understanding, at the molecular level, of factors influencing eicosanoid formation and action remains elusive. This Center comprises six research projects and two cores that will provide important insights into the role of oxygenated arachidonate species, derived either enzymatically or non-enzymatically, in human physiology and pathophysiology. A particular strength of our research program is that proposed projects integrate basic pharmacological, biochemical and molecular biological approaches with translational studies involving humans. The first Project tests the hypothesis that arachidonic acid esterified to glycerol is a novel and specific substrate for cyclooxygenase-2 and results in the formation of unique glyceryl prostaglandins (PGs). The second Project will determine the extent to which acetaminophen and salicylate exert their therapeutic efficacy by inhibiting eicosanoid production in humans. The third Project will test the hypothesis that PGE2 and PGD2 modulate the immune response to inflammation in vivo. These studies will employ mice with targeted deletions of genes encoding PG receptors. Cyclopentenone PGs such as PGJ2 have been postulated to play a role in inflammatory and proliferative responses in cells and tissues but the extent to which they are formed in vivo is unknown. The fourth Project will examine the formation and metabolism of these eicosanoids in humans. 4-hydroxynonenal is a bioactive lipid derived from the fragmentation of peroxidized arachidonic acid that is postulated to mediate adverse effects of oxidant stress. The fifth Project will focus on mechanisms by which this compound is formed in vivo and its biological effects. The sixth Project will test the hypothesis that the oxidation of cholesteryl arachidonate can be precisely defined in humans and leads to the formation of heretofore undescribed, biologically active, products containing complex cyclic structures. The investigators included in this research proposal are highly integrated both scientifically and intellectually and are extremely experienced in a number of facets of eicosanoid research. It is anticipated that the projects proposed will significantly advance our understanding of eicosanoid pharmacology and biology.
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