Characterization of Renal, Non-cyclooxygenase Arachidonate Metabolism

肾脏非环氧合酶花生四烯酸代谢的表征

基本信息

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
项目类别：
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

项目摘要

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）单加氧酶的研究现在是内源性AA生物活化的主要途径，它发现了该酶系统在细胞和器官生理学中的新且重要的功能作用。 P450衍生的代谢产物，环氧树脂和欧米茄/欧米茄-1羟基 - 羟基苯二酚的最广泛特征已与管状钠和水运输，肾脏血液动力学和肾上腺肾上管反应性的调节有关。此外，P450功能和/或表达的遗传控制改变与全身血压的控制之间的关联表明，这些酶在肾脏和身体体内平衡中以及高血压的病理生理学中的重要作用。然而，肾脏P450的生理意义及其代谢产物的位点和作用方式仍然是明确定义的，并且需要P450 AA AA单氧酶的先进实验模型，同型依赖性，功能性表型。项目2与该程序项目的细胞和器官生理组成部分结合使用，建议利用分子方法来开发和生物分子表征P450同工型依赖性功能和/或功能障碍的模型。 P450基因破坏和/或过表达将用于集成功能以及对特定肾脏的重要性和功能作用的生化分析环氧酶和欧米茄/欧米茄-1羟基酶。我们将采用分析的组合，生化和重组DNA技术，分析了p450基因依赖性eicosanoid生物合成，AA代谢和P450同工型器官表达和调节的变化。该项目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。这些重要问题的答案是为了开发有意义的方法来实现明确定义的有意义的方法：