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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：
8271446
负责人：
CRAIG R LEE
金额：
$ 33.55万
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/8271446
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 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

ABSTRACT: 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.

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