Non-Cyclooxygenase Metabolism of Arachidonic Acid

花生四烯酸的非环氧合酶代谢

• 批准号: 7758887
• 负责人: JORGE CAPDEVILA
• 金额: $ 22.68万
• 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: 2009-09-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758887
• 关键词: Address; Alkane 1-monooxygenase; Anabolism; Antihypertensive Agents; Arachidonic Acids; Biochemical; Biological; CYP4A11 gene; Cells; Chronic; Clinical; Cytochrome P450; Development; Disease; Distal; Duct (organ) structure; Eicosanoids; Enzymes; Functional disorder; Future; Genes; Genetic; Goals; Homeostasis; Homologous Gene; Hormonal; Human; Hypertension; Intervention; Ion Transport; Kidney; Kidney Diseases; Knockout Mice; Ligands; Link; Liquid substance; Mediator of activation protein; Metabolism; Mixed Function Oxygenases; Molecular; Mus; Nephrons; Organ; Pathway interactions; Phenotype; Physiological; Physiology; Plasma; Play; Process; Property; Prostaglandin-Endoperoxide Synthase; Protein Isoforms; Regulation; Renal function; Role; Signal Transduction; Site; Sodium; Sodium Chloride; Testing; Therapeutic; Transcription Coactivator; Transgenic Mice; Tubular formation; Variant; arachidonate; blood pressure regulation; epithelial Na+ channel; hemodynamics; human disease; mouse model; novel diagnostics; overexpression; pressure; prevent; programs; promoter; salt intake; salt sensitive; tool

The studies of the Cyp2c epoxygenase and Cyp4a omega-hydroxylase branches of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase pathway have uncovered important functional roles for these enzymes in cell and organ physiology. Thus, the epoxy- and hydroxy-AA products of these enzymes (EETs and 20-HETE, respectively) participate in the regulation of renal transport and hemodynamics and thus, in the control and plasma salt and volume homeostasis. Mouse models of Cyp2c44 and Cyp4a10 dysfunction show a type of hypertension that is, as with prevalent forms of the human disease, sensitive to dietary salt intake, and linked to alterations in sodium transport. Genetic studies have uncovered associations between a variant of the human CYP4A11 gene and hypertension, and suggested a role for this 20-HETE synthase in the pathophysiology of salt sensitive hypertension. However, the site and mode of action of the P450 metabolites remains to be unequivocally defined, as it is their relevance to human hypertension and renal disease. Project #1, in conjunction with the functional components of the Program Project, will utilize molecular approaches for the characterization of mouse models of P450 isoform-dependent function and/or dysfunction, and for studies of the mechanisms of action their metabolites. Gene disruption and/or overexpression will be applied to studies of the physiological and/or pathophysiological role(s) of the Cyp2c44 epoxygenase and Cyp4a12 omega-hydroxylase. In collaborafion with Projects 2-5, we will use combinations of funcfional and biochemical approaches for: a) the analysis of P45b gene-dependent changes in AA metabolism and P450 isoform organ expression and regulation, and b) studies of the relevance of their human homologues to the pathophysiology of hypertension and renal disease. Our long term goals are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answers to these important quesfions are needed for the unequivocal definition of the physiological significance of these enzymes, their roles in human diseases such as hypertension, and for the development of rational strategies for future pharmacological and/or clinical intervention.

细胞色素P450的Cyp 2c环氧酶和Cyp 4a ω-羟化酶分支的研究 （P450）花生四烯酸（AA）单加氧酶途径的研究已经揭示了这些酶的重要功能作用。 细胞和器官生理学中的酶。因此，这些酶的环氧-和羟基-AA产物（Escherichia coli 和20-HETE）参与肾转运和血液动力学的调节，因此， 控制和血浆盐和容量稳态。Cyp 2c 44和Cyp 4a 10功能障碍的小鼠模型 显示出一种高血压，与人类疾病的流行形式一样，对膳食盐敏感 摄入量，并与钠转运的改变有关。遗传学研究发现， 人CYP 4A 11基因的变异和高血压，并提出了这种20-HETE合酶的作用， 盐敏感性高血压的病理生理学。然而，P450的作用部位和作用方式 代谢物仍有待明确定义，因为它们与人类高血压和肾脏疾病的相关性 疾病项目#1将与计划项目的功能组件一起使用 用于表征P450亚型依赖性功能的小鼠模型的分子方法和/或 功能障碍，并研究其代谢物的作用机制。基因破坏和/或过表达 将应用于Cyp 2c 44的生理和/或病理生理作用的研究 环氧合酶和Cyp 4a 12 ω-羟化酶。在与项目2-5的合作中，我们将使用组合 功能和生化方法：a）分析AA中P45 b基因依赖性变化， 和B）研究它们与代谢和P450同种型器官表达和调节的相关性， 与高血压和肾脏疾病的病理生理学有关的人类同系物。我们的长期目标是 提供肾脏P450类花生酸生物学意义和作用模式的分子理解。的 这些重要问题的答案是需要明确的定义的生理 这些酶的重要性，它们在人类疾病如高血压中的作用，以及它们对发展 未来药理学和/或临床干预的合理策略。