Role of Icosaniods in Renal Function

二十烷酸在肾功能中的作用

• 批准号: 6912561
• 负责人: JORGE CAPDEVILA
• 金额: $ 170.07万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912561
• 关键词: clinical research; cytochrome P450; eicosanoid metabolism; kidney function; renal tubular transport

The kidney plays a key role in the control of body fluid volume and composition, and tubular and/or hemodymic dysfunction are common features of diseases such as stroke, hypertension, and diabetes. The CYP P450 (P450) arachidonic acid (AA) monooxygenase, a member of the AA cascade, biosynthesizes several regioisomeric hydroxyand epoxy-AA derivatives capable of modulating renal hemodynamics, tubular transport, and renovascular reactivity in vitro. Cell and animal models of P450 gene-isoform specific phenotypes, including P450 knockout mice strains, have confirmed the functional importance of these enzymes, facilitated studies of their physiological roles, and provided insights into the mechanism of action of their metabolites. By building upon these and previous studies, this application proposes: a) an integrated molecular, biochemical, and functional approach to further characterize the physiological significance of the renal AA monooxygenase, and b) to initiate the analysis of its role in the pathophysiology of human disease. For these purposes, we will continue to utilize synthetic metabolites, isoform specific inhibitors, cloned cDNAs and/or genes, and recombinant DNA and molecular genetics approaches for the study of P450isoform specific phenotypes at the cellular, organ and whole animal levels. Functional studies will include: a) biochemical documentation of P450 isoform specific changes in cell, organ, or whole animal AA metabolism b) characterization of cellular phenotypes including hormonal responses, signaling mechanisms, and ion flux and channel effects, c) the identification and characterization of hemodynamic and/or tubular effects, and d) the use of mice strains carrying disrupted P450 genes for the integration of gene specific cell and/or organ phenotypes into whole animal physiology and/or pathophysiology. The human homologues of functionally relevant murine and/or rat P450s will be identified, cloned, expressed, and characterized. High throughput sequencing will be used to define potential associations between alterations in P450 gene structure/expression and the pathophysiology of diseases such as hypertension. Our long term goals are to provide a molecular understanding of role(s) of P450 eicosanoids in renal physi ological, their mechanism and site of action, and relevance to human disease. These are needed for the development of meaningful approaches for: a) the unequivocal definition of pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention.

肾脏在控制体液体积和组成的控制中起关键作用，而管状和/或血流功能障碍是中风，高血压和糖尿病等疾病的常见特征。 CYP P450（P450）花生四烯酸（AA）单加氧酶（AA Cascade的成员）生物合成几种能够调节肾脏血液动力学，肾小管流动性和肾上管反应性的几个区域性异构体羟基和环氧树脂衍生物 体外。 p450基因相类型特异性表型的细胞和动物模型，包括P450敲除小鼠菌株，已经证实了这些酶的功能重要性，促进了其生理作用的研究，并提供了对代谢物作用机理的见解。通过基于这些和以前的研究，该应用提出：a）综合分子，生化和功能方法，以进一步表征生理 肾脏AA单加氧酶的意义，b）启动其在人类疾病病理生理学中的作用的分析。出于这些目的，我们将继续利用合成代谢物，同工型特异性抑制剂，克隆的cDNA和/或基因，以及重组DNA和分子遗传学方法在细胞，器官和整个动物水平上研究P450isoform特异性表型。功能研究将包括：a）生化 p450同工型在细胞，器官或整个动物AA代谢中的特定变化的文献b）表征细胞表型，包括激素反应，信号机制，离子通量和通道影响，c）识别和表征出血动力学和/或管状效应，以及携带的鼠标的使用，d）携带的细胞和dearn contript and Ortect and Ortect and Ornect and Ornect and Ortect and Ortect and Ortect and Ortect and Ortation contript and Ornect in Orrent in Orrent contript and Ornect in Orrume Ortation contript and Ornect contript P450肿块的使用整个动物生理学 和/或病理生理学。将确定，克隆，表达和表征与功能相关的鼠和/或大鼠P450的人类同源物。高通量测序将用于定义P450基因结构/表达的改变与高血压等疾病的病理生理学之间的潜在关联。我们的长期目标是对P450肾脏物理学的作用提供分子理解，它们的机制 和作用部位，以及与人类疾病相关。这些都是为了开发有意义的方法所需的： a）病理生理学意义的明确定义以及b）未来的药理学靶向，以及临床诊断和干预。