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.

CYP2C环氧酶和CYP4A欧米茄羟化酶分支的研究 （P450）花生四烯酸（AA）单加仑酶途径已发现了这些重要的功能作用 细胞和器官生理中的酶。因此，这些酶的环氧树脂和羟基-AA产物（EET 分别参与肾脏运输和血流动力学的调节，因此 控制和血浆盐和体积稳态。 CYP2C44和CYP4A10功能障碍的鼠标模型 与普遍的人类疾病形式一样，显示出一种高血压，对饮食盐敏感 摄入量，并与钠转运的改变有关。遗传研究发现了 人CYP4A11基因和高血压的变体，并提出了该20-Hete合酶在 盐敏感高血压的病理生理学。但是，P450的站点和作用方式 代谢物仍然是明确定义的，因为它们与人类高血压和肾脏有关 疾病。项目＃1与程序项目的功能组件结合使用，将利用 用于表征P450同工型依赖性功能的小鼠模型和/或的分子方法 功能障碍，以及研究其代谢物的作用机理。基因破坏和/或过表达 将应用于CYP2C44的生理和/或病理生理作用的研究 环氧酶和CYP4A12欧米茄羟化酶。与项目2-5合作，我们将使用组合 函数和生化方法的：a）p45b基因依赖性变化的分析 代谢和P450同工型器官的表达和调节，b）研究其相关性 人类高血压和肾脏疾病病理生理学的人类同源物。我们的长期目标是 提供对肾脏P450类eicosanoid生物学意义和作用方式的分子理解。这 对于生理的明确定义，需要对这些重要问题的答案 这些酶的意义，它们在高血压等人类疾病中的作用以及发育 未来药理和/或临床干预的理性策略。