BIOLOGY OF PROGRESSIVE DESTRUCTION

渐进性破坏的生物学

• 批准号: 6176482
• 负责人: RAYMOND C. HARRIS
• 金额: $ 68.95万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176482
• 关键词: kidney disorder; pathologic process; prostaglandin endoperoxide synthase; renal failure

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.

导致肾脏疾病进展的一些危险因素 确认了这一点，许多人已经做出了重大努力 调查人员将阐明重要机制和关键调节因素 对肾单位的逐渐破坏负责。机制清单 而且潜在的调解人很大。我们选择了探索中部 酶、环氧合酶及其产物在 进行性肾单位破坏的原因有很多。首先，有 充分的证据表明，许多假定的机制，当然还有 大多数被提出的进行性肾损害的多肽介质是 与环氧合酶产物的形成密切相关 肾脏的某些区域。其次，有证据表明，相对原始的 在疾病的肾脏中抑制环氧合酶的手法， 环氧合酶产物可能是有益的，就像在 保护肾脏血流(从长远来看，这是有益的吗？)或 有害的，如蛋白尿，可以减少 通过抑制环氧合酶的作用。第三，必要的关键工具 解决环氧合酶途径现在是可用的，确实，有些已经 由该中心的参与者开发。量化与结构 环氧合酶的产物形成验证、评价 基因水平、分子水平上的活性及其调控 环氧合酶产物对胞外影响的表征 该中心拨款中提出的基质蛋白和其他方法包括 有必要确定环氧合酶可能发挥的核心作用 及其产品在肾脏疾病进展中的作用。世界上的发展 二十烷基类受体的分子生物学及其研究进展 特定激动剂和拮抗剂的药理学将提供可行的方法 进行干预。该中心由四个项目和四个核心组成，一个 三是管理，三是科学。在探索联系的过程中 花生四烯酸环氧合酶及其代谢产物的相互作用 进行性肾脏疾病，该中心提出了一种广泛的体内和体内 进展性肾单位免疫和非免疫模型的体外研究 毁灭。体内和体外功能研究，生化研究， 分子生物学方法也都在计划之中。项目#1专注于 主要研究环氧合酶和花生四烯酸代谢产物的作用 该酶在大鼠炎性和非炎性免疫损伤模型中的作用 老鼠肾。项目2侧重于体内和体外研究 对残肾模型进展的检查提供了见解 环氧合酶的作用。项目3是一项专门的体外试验。 专注于肾小球内皮细胞和内脏上皮细胞的项目。 最后，项目#4关注的是残肾模型中的小管。这个 三个科学核心与所有四个项目相互作用，提供 花生四烯酸代谢物测定和结构的分析支持 验证、结构和定量形态测量支撑和支撑 细胞外基质的生物化学和分子表征 组件。我们认为，该中心的调查人员代表着 将专注于强大而独特的技术和兴趣的融合 在一个非常重要的问题上，即环氧合酶代谢产物的作用 花生四烯酸在进行性肾单位破坏中的作用。