BIOLOGY OF PROGRESSIVE NEPHRON DESTRUCTION

许多肾脏疾病进展的风险因素已被 已经确定，并已作出重大努力的一部分，许多 研究人员阐明重要机制和关键介质 导致肾单位的逐步破坏 机制清单 和潜在的介质是大的。 我们选择了探索中央 酶、环氧合酶及其产物可能在 进行性肾单位破坏的原因有很多。 一是 大量的证据表明，许多假设的机制，当然， 大多数提出的进行性肾损伤的肽介质是 在某些情况下，与环氧合酶产物的形成密切相关 肾脏的区域。 第二，有证据表明， 在患病肾脏中， 环氧合酶产品可能是有益的，如在 保持肾血流（从长远来看这是有益的吗？）或 有害的，如在蛋白尿的情况下， 环氧合酶抑制的幅度。 第三，关键工具， 解决环氧合酶途径现在可用，事实上，有些已经 由本中心的参与者开发。 定量和结构 产物形成的验证，环氧合酶的评价 活性及其在遗传水平上的调节，分子 环氧合酶产物对细胞外 基质蛋白，和其他方法提出了在这个中心赠款是 有必要确定什么可能是环氧化酶的核心作用 及其产物在肾脏疾病进展中的作用。 的发展 类花生酸受体的分子生物学及其研究进展 特异性激动剂和拮抗剂的药理学将提供 干预 该中心由四个项目和四个核心组成， 三是行政性，三是科学性。 在探索 环氧合酶及其代谢产物花生四烯酸与 进行性肾脏疾病，该中心提出了一个广泛的体内和 进行性肾单位的免疫和非免疫模型的体外方法 杀伤性 体内和体外功能研究，生化研究， 和分子生物学方法都在计划中。 项目#1聚焦 主要是环氧合酶和花生四烯酸代谢物的作用， 这种酶在炎症和非炎症免疫损伤模型中， 老鼠的肾脏 项目#2关注体内和体外 检查残余肾模型中的进展，提供见解 环氧合酶的作用。 项目#3仅为体外 项目重点是肾小球内皮细胞和内脏上皮细胞。 最后，项目#4关注残余肾模型中的小管。 的 三个科学核心与所有四个项目相互作用， 用于花生四烯酸代谢物测量和结构的分析支持 验证、结构和定量形态测定支持，以及 在细胞外基质的生化和分子特征方面， 件. 我们认为，该中心的调查人员代表了一个 强大而独特的融合技术和利益，将集中 一个非常重要的问题，即环氧化酶代谢物的作用， 花生四烯酸在进行性肾单位破坏中的作用

A number of risk factors for progression of renal disease have been identified and there has been a major effort on the part of many investigators to elucidate the important mechanisms and key mediators responsible for progressive nephron destruction. The list of mechanisms and potential mediators is large. We have chosen to explore the central role that the enzyme, cyclooxygenase, and its products may play in progressive nephron destruction for a number of reasons. First, there is ample evidence that many of the postulated mechanisms and certainly the majority of the proposed peptide mediators of progressive renal damage are intimately intertwined with cyclooxygenase product formation in certain regions of the kidney. Second, there is evidence from the relatively crude maneuver of cyclooxygenase inhibition that in diseased kidneys, cyclooxygenase products may be either beneficial, as in the case of preserving renal blood flow (is this beneficial in the long run?) or detrimental, as in the case of proteinuria which can be reduced in magnitude by cyclooxygenase inhibition. Third, critical tools necessary to address the cyclooxygenase pathway are now available and, indeed, some have been developed by participants in this Center. Quantitation and structural verification of product formation, evaluation of cyclooxygenase enzyme activity and its regulation at the genetic level, molecular characterization of the effects of cyclooxygenase products on extracellular matrix proteins, and other approaches proposed in this Center grant are necessary to define what is likely to be a central role for cyclooxygenase and its products in the progression of renal disease. Developments in the molecular biology of eicosanoid receptors and developments in the pharmacology of specific agonists and antagonists will make available ways to intervene. This Center is composed of four projects and four cores, one being administrative and three being scientific. In exploring the link between cyclooxygenase and its metabolites of arachidonic acid with progressive renal disease, this Center proposes a broadbased in vivo and in vitro approach to both immune and non-immune models of progressive nephron destruction. In vivo and in vitro functional studies, biochemical studies, and molecular biologic approaches are all planned. Project #1 focuses predominantly on the role of cyclooxygenase and arachidonate metabolites of this enzyme in models of inflammatory and non-inflammatory immune injury in the rat kidney. Project #2 focuses on both in vivo and in vitro examination of progression in the remnant kidney model providing insights into the role of cyclooxygenase. Project #3 is exclusively an in vitro project focusing on glomerular endothelial, and visceral epithelial cells. Finally, Project #4 focuses on the tubule in the remnant kidney model. The three scientific cores interact with all four of the projects providing analytic support for arachidonate metabolite measurements and structural verification, structural and quantitative morphometry support, and support in the biochemical and molecular characterization of extracellular matrix components. We believe that the investigators in this Center represent a powerful and unique blend of techniques and interests that will be focused on a very important issue, i.e. the role of cyclooxygenase metabolites of arachidonic acid in progressive nephron destruction.