ICOSANOIDS AND RENAL FUNCTION

肾在津液的控制中起着核心作用。 组成。细胞色素P450(P450)依赖的花生四烯酸 单加氧酶现在被认为是生物医学中的一种成分 重要的AA级联。丰富的文献数据暗示P450来源 二十烷酸类化合物在肾功能的各个方面，以及在 实验性高血压的病理生理学。然而，大多数人 这些研究的描述性性质以及适当的 实验工具排除了明确的特定任务 对P450二十烷酸的功能和/或作用机制，以及 目前肾脏P450的特性研究进展，以提供一个 综合分子、生化、生物物理和功能方法 生理和/或病理生理学的描述 肾脏AA单加氧酶的意义。异构体特异性代谢物 抑制剂，克隆的cDNA和/或基因，以及重组DNA方法将是 用于P450-异构体特异性的分子表征 在细胞、器官和整个动物水平上的表型。功能性 研究将包括：a)P450亚型的生化记录 细胞或整个动物AA代谢的特殊变化b)特征 包括激素反应、信号机制在内的细胞表型 以及离子通量和通道效应，c)识别和 血流动力学和/或管状效应的特征，以及d)使用 携带突变P450基因的小鼠品系进行基因特异性整合 细胞和/或器官表型与整个动物生理和/或 病理生理学。该项目的长期目标是提供一个 从分子水平认识肾P450二十烷类化合物的生物学意义 和行动模式。这些重要问题的答案是 制定有意义的办法以：a)明确的定义 它们的病理生理学意义，以及b)随后 药理学和/或临床干预。

The kidney play a central role in the control of body fluid and composition. The cytochrome P450 (P450)- dependent arachidonic acid (AA) monooxygenase is now recognized as a component of the biomedically important AA cascade. Abundant literature data implicate P450-derived eicosanoids in various aspects of kidney function, as well as in the pathophysiology of experimental hypertension. However, the mostly descriptive nature of these studies and a paucity of appropriate experimental tools has precluded unequivocal assignments of specific functions and/or mechanisms of action to the P450 eicosanoids, as well as current on progress in the characterization of kidney P450s, to offer an integrated molecular, biochemical, biophysical and functional approach to the delineation of the physiological and/or pathophysiological significance of the renal AA monooxygenase. Metabolites, isoform specific inhibitors, cloned cDNAs and/or genes, and recombinant DNA methods will be utilized for the molecular characterization of P450-isoform specific phenotypes at the cellular, organ and whole animal levels. Functional studies will include: a) biochemical documentation of P450 isoform specific changes in cell 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 with mutated P450 genes for the integration of gene specific cell and/or organ phenotypes into whole animal physiology and/or pathophysiology. The long term goals of this project are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answer to these important questions are needed for the development of meaningful approaches to: a) the unequivocal definition of their pathophysiological significance, and b) subsequent pharmacological and/or clinical interventions.