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Cytochrome P450 Derived Eicosanoids and Inflammation

细胞色素 P450 衍生的类二十烷酸与炎症

基本信息

批准号：
8071142
负责人：
CRAIG R LEE
金额：
$ 30.29万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071142
关键词：
Acids Acute Alkane 1-monooxygenase Anabolism Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Attenuated Biochemical Biological Assay Blood Vessels CYP2J2 gene Cardiovascular system Cell Adhesion Cell Adhesion Molecules Chemosensitization Cytochrome P450 Data Development Disease Eicosanoids Endothelial Cells Enzyme-Linked Immunosorbent Assay Epoxide hydrolase Equilibrium Exhibits Functional disorder Generations Genetic Transcription Health Hepatic Hepatic Tissue Histologic Human Hydrolysis Hydroxyeicosatetraenoic Acids Immunoblotting In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Knockout Mice Laboratories Leukocytes Lipopolysaccharides Maintenance Mediating Mediator of activation protein Metabolic Metabolism Mixed Function Oxygenases Molecular Molecular Biology Mus NF-kappa B Nitric Oxide Synthase Pathogenesis Pathologic Processes Pathway interactions Peroxidases Play Process Prostaglandin-Endoperoxide Synthase Regulation Relative (related person)Research Project Grants Reverse Transcriptase Polymerase Chain Reaction Role Series Signal Transduction Stimulus Techniques Testing Therapeutic Tissues Transcriptional Activation Transgenic Mice Transgenic Organisms Vascular Endothelial Cell Vasoconstrictor Agents Wild Type Mouse Work Xenobiotic Metabolism attenuation base chemokine cytochrome P-450 CYP2C subfamily cytokine defined contribution eicosanoid metabolism in vivo inhibitor/antagonist novel novel strategies novel therapeutics overexpression promoter protein expression research study tool transcription factor vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Inflammation is a fundamental process which plays an integral role in the pathogenesis of numerous disease states in humans. Nuclear factor kappa B (NF-?B) is a central mediator of the inflammatory response via transcriptional activation of cytokine, chemokine and cellular adhesion molecule expression. Consequently, identification of novel strategies aimed at inhibition of this pathological process offers substantial therapeutic potential. Arachidonic acid is oxidatively metabolized by cytochrome P450 (CYP) epoxygenases from the CYP2J and CYP2C subfamilies to epoxyeicosatrienoic acids (EETs) in hepatic and extra-hepatic tissue. The EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to less active dihydroxyeicosatrienoic acids (DHETs). Arachidonic acid is also metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) by CYP ?-hydroxylases from the CYP4A and CYP4F subfamilies. Recent evidence has demonstrated that CYP-derived EETs and 20-HETE possess anti- and pro-inflammatory effects, respectively. However, the contribution of CYP-mediated eicosanoid metabolism to the regulation of inflammation in vivo has not been rigorously characterized. We hypothesize that the functional balance between CYP epoxygenase- and CYP ?-hydroxylase-mediated arachidonic acid metabolism is integral to the regulation of NF-?B-mediated inflammatory responses in vivo, and modulation of this balance in favor of the CYP epoxygenase pathway offers substantial therapeutic potential. The primary objectives of this proposal are to: (1) define the impact of the inflammatory response on hepatic and extra-hepatic CYP-mediated eicosanoid metabolism, (2) define the functional role of CYP epoxygenase-mediated EET biosynthesis and sEH-mediated EET hydrolysis in the regulation of inflammation, and (3) characterize the relative impact of CYP epoxygenase and CYP ?-hydroxylase pathway modulation on inflammatory responses in vivo. This project will utilize novel transgenic and knock-out mice and pharmacological tools to manipulate CYP-mediated eicosanoid metabolism in vivo, while characterizing NF-?B-mediated inflammatory responses using established molecular biology and analytical techniques. Collectively, this series of novel experiments will define the mechanistic contribution of CYP epoxygenase-derived EETs and CYP ?-hydroxylase-derived 20-HETE to the regulation of hepatic and extra-hepatic inflammatory responses in vivo, and facilitate the development of new anti-inflammatory strategies with potential therapeutic application to numerous disease states in humans. PUBLIC HEALTH RELEVANCE: Inflammation is a fundamental process which plays an integral role in the pathogenesis of numerous diseases in humans. Completion of this research project will define the contribution of cytochrome P450-mediated eicosanoid metabolism to the regulation of inflammation in vivo, characterize the underlying mechanisms, and facilitate the development of novel therapeutic strategies aimed at inhibition of inflammation.

描述(由申请人提供)：炎症是一个基本的过程，在人类许多疾病的发病机制中发挥着不可或缺的作用。核因子-kappaB是炎症反应的中枢介质，通过转录激活细胞因子、趋化因子和细胞黏附分子的表达。因此，识别旨在抑制这一病理过程的新策略提供了巨大的治疗潜力。花生四烯酸在肝脏和肝外组织中被细胞色素P450(CYP)环氧合酶氧化代谢成环氧二十碳三烯酸(EETs)。EETs被可溶性环氧化物水解酶(SEH)迅速水解为活性较低的二羟基二十碳三烯酸(DHETs)。花生四烯酸也被细胞色素P4A和细胞色素P4F亚家族的CYP？-羟基酶代谢成20-羟基二十碳四烯酸(20-HETE)。最近的证据表明，CYP来源的EETs和20-HETE分别具有抗炎和促炎作用。然而，CYP介导的二十烷类化合物代谢对体内炎症调节的贡献还没有得到严格的表征。我们推测，CYP环氧合酶和CYP羟基酶介导的花生四烯酸代谢之间的功能平衡是调节体内核因子B介导的炎症反应所不可或缺的，这种平衡的调节有利于CYP环氧合酶途径提供了巨大的治疗潜力。本研究的主要目的是：(1)明确炎症反应对肝脏和肝外CYP介导的二十烷类化合物代谢的影响；(2)明确CYP环氧合酶介导的EET生物合成和sEH介导的EET水解酶在调节炎症反应中的功能作用；(3)研究CYP环氧合酶和CYP-羟基酶途径调控对体内炎症反应的相对影响。该项目将利用新型转基因和基因敲除小鼠和药理学工具在体内操纵CYP介导的二十烷类化合物代谢，同时利用成熟的分子生物学和分析技术表征NF-B介导的炎症反应。总之，这一系列新颖的实验将确定CYP环氧合酶衍生的EETs和CYP？-羟基酶衍生的20-HETE在体内调节肝脏和肝外炎症反应中的机制贡献，并促进新的抗炎策略的开发，这些策略具有潜在的治疗人类多种疾病的应用。与公共卫生相关：炎症是一个基本的过程，在人类许多疾病的发病机制中发挥着不可或缺的作用。这项研究项目的完成将确定细胞色素P450介导的二十烷类代谢对体内炎症调节的贡献，表征潜在的机制，并促进旨在抑制炎症的新治疗策略的开发。