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：
8304582
负责人：
CRAIG R LEE
金额：
$ 2.85万
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/8304582
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）：炎症是一个基本过程，在人类众多疾病状态的发病机理中起着不可或缺的作用。核因子Kappa B（NF-？B）是通过细胞因子，趋化因子和细胞粘附分子表达的转录激活炎症反应的中心介体。因此，旨在抑制这种病理过程的新型策略的鉴定提供了巨大的治疗潜力。小蛛网酸被氧化作用，由CYP2J和CYP2C亚家族的细胞色素P450（CYP）环氧酶氧化为肝和肝外组织中的环氧酸性酸（EET）。 EET通过可溶性环氧化物水解酶（SEH）迅速水解为活性较低的二羟基乙酸酸酯（DHETS）。蛛网膜酸还通过CYP4A和CYP4F亚家族的CYP？ - 羟基酶代谢为20-羟基乙烯酸（20-己）。最近的证据表明，CYP衍生的EET和20-HETE分别具有抗炎作用。然而，CYP介导的类花生酸代谢对体内炎症调节的贡献尚未得到严格的特征。我们假设CYP上氧合酶 - 和CYP之间的功能平衡是 - 羟化酶介导的蛛网膜化代谢是体内NF- b- b介导的炎症反应的不可或缺的一部分巨大的治疗潜力。该提案的主要目的是：（1）定义炎症反应对肝和肝外CYP介导的eicosanoid代谢的影响，（2）定义CYP上氧合酶介导的EET生物合成和SEH介导的EET的功能作用炎症调节中的水解，以及（3）表征CYP环氧酶和CYP？ - 羟化酶途径对体内炎症反应的相对影响。该项目将利用新型的转基因和敲除小鼠以及药理学工具在体内操纵CYP介导的eicosanoid代谢，同时使用已建立的分子生物学和分析技术来表征NF-？B介导的炎症反应。总的来说，这一系列新型实验将定义CYP氧化酶衍生的EET和CYP？ - 羟化酶衍生的20-HETE对体内肝和肝外炎症反应的调节的机理贡献，并促进新的抗 - 炎症策略具有潜在的治疗性应用于人类的众多疾病状态。公共卫生相关性：炎症是一个基本过程，在人类众多疾病的发病机理中起着不可或缺的作用。该研究项目的完成将定义细胞色素p450介导的类固醇代谢对体内炎症调节的贡献，表征基本机制，并促进旨在抑制炎症的新型治疗策略。