Characterization of Renal, Non-cyclooxygenase Arachidonate Metabolism

肾脏非环氧合酶花生四烯酸代谢的表征

• 批准号: 7459639
• 负责人: JORGE CAPDEVILA
• 金额: $ 17.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459639
• 关键词: Address; Alkane 1-monooxygenase; Anabolism; Animal Model; Arachidonic Acids; Biochemical; Biological; Blood Pressure; Cells; Clinical; Collaborations; Cytochrome P450; Development; Disruption; Eicosanoids; Enzymes; Experimental Models; Functional disorder; Future; Genes; Genetic; Goals; Homeostasis; Homologous Gene; Hormonal; Human Identifications; Hypertension; Intervention; Ion Channel; Ion Transport; Kidney; Knockout Mice; Liquid substance; Mediating; Metabolism; Mixed Function Oxygenases; Modeling; Molecular; Molecular Genetics; Mus; Organ; Participant; Pathway interactions; Phenotype; Physiological; Physiology; Process; Prostaglandin-Endoperoxide Synthase; Protein Isoforms; Protein Overexpression; Recombinant DNA; Regulation; Renal function; Role; Role playing therapy; Signal Transduction; Site; Sodium; System; Techniques; Tubular formation; Water; arachidonate; cyclooxygenase 1; cyclooxygenase 2; enzyme mechanism; hemodynamics; human disease; kidney vascular structure; programs; promoter; salt sensitive

The studies of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase, now established as a major pathway for the bioactivation of endogenous AA, uncovered new and important functional roles for this enzyme system in cell and organ physiology. The most extensively characterized of the P450-derived metabolites, the epoxy- and the omega/omega-1 hydroxy-arachidonic acid, have been implicated in the regulation of tubular sodium and water transport, renal hemodynamics, and renovascular reactivity. Furthermore, associations between genetically controlled alterations in P450 function and/or expression, and the control of systemic blood pressures suggest important roles for these enzymes in kidney and body homeostasis, and in the pathophysiology of hypertension. However, the physiological significance of renal P450 and the site and mode of action of its metabolites remains to be unequivocally defined, and there is a need for advanced experimental models of P450 AA Monooxygenase, isoform-dependent, functional phenotypes. Project 2, in conjunction with the cell and organ physiology components of this Program Project, proposes to utilize molecular approaches for the development and bio-molecular characterization of models of P450 isoform-dependent function and/or dysfunction. P450 gene disruption and/or overexpression will be employed for the integrated functional and biochemical analysis of the significance and the functional role(s) of specific kidney AA epoxygenase and omega/omega-1 hydroxylases. We will apply a combination of analytical, biochemical, and recombinant DNA techniques to the analysis of P450 gene-dependent changes in eicosanoid biosynthesis, AA metabolism, and P450 isoform organ expression and regulation. The long term goals of this project are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answers to these important questions are needed for the development of meaningful approaches to the unequivocal definition of: a) their physiological significance, b) relevance to the human diseases such as hypertension, and for the development of rational strategies for future pharmacological and/or clinical intervention.

细胞色素P450（P450）花生四烯酸（AA）单加氧酶，现在被确立为内源性AA的生物激活的主要途径，研究发现，新的和重要的功能作用，这种酶系统在细胞和器官生理学。最广泛表征的P450衍生的代谢物，环氧-和ω/ω-1羟基-花生四烯酸，已涉及肾小管钠和水转运，肾血流动力学和肾血管反应性的调节。此外，P450功能和/或表达的遗传控制改变与全身血压控制之间的关联表明这些酶在肾脏和身体稳态以及高血压的病理生理学中具有重要作用。然而，肾脏P450的生理意义及其代谢产物的作用位点和方式仍有待明确定义，并且需要P450 AA单加氧酶、亚型依赖性、功能表型的高级实验模型。项目2与本项目的细胞和器官生理学部分结合，提出利用分子方法开发和生物分子表征P450亚型依赖性功能和/或功能障碍模型。P450基因破坏和/或过表达将用于整合的功能性表达。 和生化分析的意义和功能作用的特定肾脏AA（S） 环氧酶和ω/ω-1羟化酶。我们将结合分析， 生物化学和重组DNA技术来分析类花生酸生物合成、AA代谢和P450同种型器官表达和调节中的P450基因依赖性变化。该项目的长期目标是提供对肾脏P450类花生酸生物学意义和作用模式的分子理解。这些重要问题的答案是发展有意义的方法来明确定义：a）其生理意义，B）与人类疾病，如高血压的相关性，并为未来的药理学和/或临床干预的合理策略的发展。