ROLE OF ICOSANOIDS IN RENAL FUNCTION

近六年来NAOPH依赖的细胞色素P-450 花生四烯酸的代谢越来越重要。 该计划项目赠款代表了一种独特的合作 旨在表征这一途径的生物化学及其 对肾脏的整体重视。六个独立的但 建议的免费项目：1)交通影响 花生四烯酸在确定的肾单位节段中产生P-450代谢物。那里 现在有充分的理由相信P-450代谢物具有重要的 有机近端小管钠转运的功能效应 近端小管的离子分泌，延髓的盐分转运 粗大的Henle升支和加压素调节的水流 在皮质收集小管中。项目1将继续寻找这些地点 以及这些直接肾小管作用的机制。2) 肾脏细胞色素P-450花生四烯酸代谢的特征。 这个项目将描述花生四烯酸的生物化学。 从酶学、代谢物形成、结构 肾脏的特征、调节和定位。 这些研究对功能研究是至关重要的。3)角色 人血小板膜细胞色素P-450花生四烯酸代谢产物 他们的聚集地。血小板聚集和释放 生物活性物质在肾脏疾病中的重要作用 疾病。基于最近证明的潜在影响 作为一种关于血小板聚集的P-450代谢物，这个项目将 鉴定人血小板中的P-450氧化产物，确定 它们在血小板脂质中的酯化作用，检查它们对 激动剂诱导的血小板聚集，检测它们从 活化的血小板，并确定它们的机制 抑制血小板聚集。4)P-450的体内研究 代谢物。研究将测试它们对肾功能的影响 在大鼠体内利用清除和显微穿刺法研究。 P-450代谢深刻调控的初步数据 实验性模型，如单侧肾切除术、糖尿病和 怀孕将被追查。5)模型细胞的表征 研究细胞色素P-450花生四烯酸代谢产物的系统测试 它们对信号转导通路的影响，并确定 它们是否充当细胞内的第二信使。6) 肾P-450二十烷类化合物的表征和合成 开发合成代谢物和 用于生物评价的抑制剂。我们觉得这些项目 代表了技术和调查人员的理想集成 肾细胞色素P-450的生物学意义 花生四烯酸代谢。

Over the past six years the NAOPH dependent cytochrome P-450 metabolism of arachidonic acid has assumed increasing importance. This Program Project Grant represents a unique collaboration designed to characterize the biochemistry of this pathway and its overall importance to the kidney. Six independent but complimentary projects are proposed: 1) Transport effects of arachidonate P-450 metabolites in defined nephron segments. There is now good reason to believe that P-450 metabolites have important functional effects on sodium transport in proximal tubule, organic ion secretion in proximal tubule, salt transport in the medullary thick ascending limb of Henle, and vasopressin modulated water flow in the cortical collecting tubule. Project 1 will pursue the sites and mechanisms of these direct tubular actions. 2) characterization of renal cytochrome P-450 arachidonate metabolism. This project will characterize the biochemistry of arachidonic acid oxidation in terms of enzymology, metabolite formation, structural characterization, regulation, and localization in the kidney. These studies are critical to the functional studies. 3) Role of cytochrome P-450 arachidonate metabolites in human platelets and their aggregation. Platelet aggregation and release of biologically active products plays an important role in renal disease. Based on the recent demonstration of potent effects of a P-450 metabolite on platelet aggregation, this project will identify P-450 oxygenation products in human platelets, determine their esterification in platelet lipids, examine their effects on agonist induced platelet aggregation, examine their release from activated platelet and determine the mechanism by which they inhibit platelet aggregation. 4) In vivo studies of P-450 metabolites. Studies will test their effects on renal function in vivo utilizing clearance and micropuncture studies in the rat. Preliminary data on profound modulation of P-450 metabolism in experimental models such as unilateral nephrectomy, diabetes, and pregnancy will be pursued. 5) Characterization of a model cell system to study cytochrome P-450 arachidonate metabolites to test their effects on signal transduction pathways, and to determine whether they serve as intracellular second messenger. 6) Characterization and synthesis of renal P-450 eicosnoids, development of strategies to synthesize the metabolites and inhibitors for biological evaluation. We feel that these projects represent an ideal integration of techniques and investigators to address the biological importance of renal cytochrome P-450 arachidonate metabolism.