CELL AND MOLECULAR PATHOBIOLOGY OF RENAL DISEASE

肾病的细胞和分子病理学

• 批准号: 6124713
• 负责人: JON S MORROW
• 金额: $ 114.03万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124713
• 关键词: cell adhesion molecules; cytoskeleton; renal ischemia /hypoxia; tight junctions

DESCRIPTION (Abstract of the application) This application seeks support for a broad program in renal research directed at understanding the cellular molecular mechanisms of renal disease. The emphasis of the program is on understanding the pathophysiologic basis of the kidney's response to acute ischemic injury. Crucial to this understanding is the fundamental knowledge of the molecular cell biological processes governing the establishment of polarity in both renal epithelial and endothelial cells, the mechanisms by which the barrier functions of both epithelium and endothelium are maintained, and the response of these tissues to the stress of acute ischemic injury. This investigation will be carried out under the aegis of four complementary and integrated projects, supported by three Core programs. The areas of focus include: 1) endothelial cell differentiation and permeability control in the renal microvasculature, as guided by the adhesion molecules ZO-1, PECAM and VE-cadherin; 2) the regulation of cortical and Golgi spectrin-actin cytoskeletal organization, and their role in establishing and maintaining Na,K-ATPase and E-cadherin polarity in renal epithelial cells; 3) the identity and role of the renal myosins, their interaction with the renal cell actin skeleton and their role in membrane trafficking and the establishment of polarity; and 4) the mechanisms establishing and maintaining tight-junctional polarity and integrity, focusing on the role of renal occludin as an adhesion molecule and its interactions with the cytoskeleton. Experiments will be carried out both in renal cell culture systems, including cultures of endothelial cells, and in established renal lines such as MDCK and LLC-PK1 cells. Renal injury in both wild type (WT) and genetically modified mice will also be studied. The core facilities, which will support this program, include a sophisticated imaging core and an in vivo renal injury core. Synergies within the group, a focus on fundamental knowledge, a planned program of external review, monthly research in progress meetings, and a robust seminar series collectively assure maximal opportunities for discovery. Understandings of significant relevance to renal disease are assured.

描述（应用摘要）本应用程序寻求支持一项肾脏研究的广泛计划，该计划旨在了解肾脏疾病的细胞分子机制。该计划的重点在于理解肾脏对急性缺血性损伤反应的病理生理基础。对这种理解至关重要的是肾上皮细胞和内皮细胞中极性建立的分子细胞生物学过程的基本知识，即维持上皮和内皮的障碍功能的机制，以及这些组织对这些组织对急性不足性损伤的压力的反应。这项调查将在四个互补项目和综合项目的主持下进行，并得到三个核心计划的支持。重点区域包括：1）在肾小管肾小管系统中的内皮细胞分化和渗透性控制，在粘附分子ZO-1，PECAM和VE-Cadherin的指导下； 2）调节皮质和高尔基细胞 - 肌动蛋白细胞骨架组织，以及它们在肾上皮细胞中建立和维持Na，k-atpase和E-钙粘着蛋白极性中的作用； 3）肾脏肌球蛋白的身份和作用，它们与肾细胞肌动蛋白骨骼的相互作用及其在膜运输和极性建立中的作用； 4）建立和维持紧密连接的极性和完整性的机制，重点是肾闭塞物作为粘附分子的作用及其与细胞骨架的相互作用。实验将在肾细胞培养系统（包括内皮细胞的培养物以及诸如MDCK和LLC-PK1细胞）的既定肾脏线中进行。还将研究野生型（WT）和转基因小鼠的肾脏损伤。支持该程序的核心设施包括复杂的成像核心和体内肾脏损伤核心。该小组中的协同作用，关注基本知识，计划的外部审查计划，每月研究会议的研究以及强大的研讨会系列，共同确保了发现最大机会的机会。确保与肾脏疾病有重大相关性的理解。