Convergence of the COX-2 and 5-lipoxygenase pathways

COX-2 和 5-脂氧合酶途径的融合

• 批准号: 7938289
• 负责人: Claus Schneider
• 金额: $ 5.51万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938289
• 关键词: Active Sites; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Arterial Fatty Streak; Aspirin; Asthma; Atherosclerosis; Attenuated; Binding; Binding Sites; Biological Process; Biology; Carbon; Cells; Commit; DNA Sequence Rearrangement; Detection; Dinoprostone; Disease; Eicosanoids; Endothelial Cells; Enzymatic Biochemistry; Enzymes; Etiology; Family; Genetic Crossing Over; Human; Hydrogen Peroxide; Hydroxyeicosatetraenoic Acids; Inflammation; Inflammatory; Inflammatory Response; Interleukin-8; Isoenzymes; Kinetics; Lead; Leukotriene A4; Leukotrienes; Light; Link; Lipoxins; Lipoxygenase; Lung; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolism; Mus; Pathway interactions; Peritoneal Macrophages; Peroxides; Pharmaceutical Preparations; Property; Prostaglandin D2; Prostaglandin H2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Psoriasis; Reaction; Regulation; Resolution; Route; Series; Signal Pathway; Single Parent; Substrate Specificity; Testing; Tissues; Treatment Protocols; analog; angiogenesis; arachidonic acid 5-hydroperoxide; base; cancer type; cyclooxygenase 1; cyclooxygenase 2; macrophage; mast cell; novel; novel therapeutics

There is strong evidence for the induction of the inflammatory enzymes 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) in atherosclerosis, asthma, and many types of cancer. Both enzymes mediate the inflammatory response of these diseases through the synthesis of leukotrienes and prostaglandins, respectively. The leukotriene and prostaglandin pathways have traditionally been viewed as independent biosynthetic routes since the committed step toward either pathway is taken as the initial oxygenation of the common substrate, arachidonic acid. This proposal is based on the finding that the 5-LOX product, 5S- hydroxyeicosatetraenoic acid (5S-HETE), is a selective and highly efficient substrate for oxygenation by COX-2 (but not by the COX-1 isozyme). The discovery of this novel substrate for COX-2 intimately links the two eicosanoid pathways. The common 5-LOX/COX-2 product is a novel di-endoperoxide that is structurally reminiscent of, but distinctly different from prostaglandin H2. In the first Specific Aim we propose to analyze the enzymology of the conversion of arachidonic acid into the novel di-endoperoxide by establishing the reaction kinetics, substrate specificity, and the structural basis for binding of 5-HETE in the COX-2 active site. The enzymatic transformation of the di-endoperoxide product will be studied using RAW264.7 cells and murine peritoneal macrophages, prototypical cells that expresses both 5-LOX and COX-2. Endogenous formation of the novel eicosanoid and its family of metabolites will be assessed in mouse atherosclerotic tissue. We will test the hypothesis that the novel di-endoperoxide (or its metabolites) possess anti- inflammatory properties. Preliminary studies have shown that the di-endoperoxide attenuates the release of interleukin-8 from stimulated mast cells and microvascular endothelial cells. The signaling pathways involved in this interaction will be studied using the 5-LOX and COX-2 expressing HMC-1 human mast cell. Characterization of the novel 5-LOX/COX-2 cross-over pathway will undoubtedly lead to an entirely new understanding of the biology of 5-LOX and COX-2, and it will also shed new light on the etiology and regulation of the inflammatory component of diseases like atherosclerosis, asthma, and cancer. These studies could ultimately lead to new therapeutic regimens for the treatment of these diseases using established anti-inflammatory medications.

有强有力的证据表明，炎症酶5-脂氧合酶（5-LOX）和