HGF receptor and renal cell survival and differentiation

HGF受体与肾细胞存活和分化

• 批准号: 6774787
• 负责人: YOUHUA LIU
• 金额: $ 25.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774787
• 关键词: SDS polyacrylamide gel electrophoresis; apoptosis; cell death; cell differentiation; epithelium; gene targeting; genetically modified animals; growth factor receptors; hepatocyte growth factor; immunocytochemistry; kidney cell; kidney disorder; laboratory mouse; receptor expression; renal tubule; southern blotting; terminal nick end labeling; tissue /cell culture; transfection; western blottings

This competitive renewal application is a continuation of our long-term effects to understand the role and mechanism of hepatocyte growth factor (HGF) and its c-met receptor in normal and diseased kidney. Studies in previous project period of this application suggest that HGF and its c-met receptor may play an important role in tubule survival, repair and regeneration as well as in the maintenance of tubular cell differentiated status in adult kidney. In this continuation application, we propose to create a conditional knockout mouse model, in which the c-met receptor gene is null-mutated specifically in renal tubular epithelial cells in the kidney. By using this model system, we will test the hypothesis that HGF/c-met is a major signaling system in the control of renal cell survival and differentiation in numerous physiologic and pathophysiologic settings. These studies will be accomplished in the three specific aims. In aim 1, we will investigate the dependence of cell survival on cellular abundance of c-met receptor; and unravel the novel mechanism underlying HGF-independent cytoprotection of renal tubular epithelial cells by c-met receptor. In aim 2, we will investigate the rate and extents of tubular cell death and renal functions in tubule-specific c-met conditional knockout mice both under normal conditions and after acute renal injury. In aim 3, we will investigate and compare the phenotypes of renal tubular epithelia in tubule-specific c-met conditional knockout mice under normal conditions as well as in chronically injured kidney induced by unilateral ureteral obstruction. These studies will provide fundamental and important insights into understanding the mechanism controlling tubular cell survival, repair and differentiation under normal and diseased conditions. Ultimately, these studies may lead to development of novel strategies to alter the course of human renal disease by manipulating the activities of HGF/c-met signaling system.

这种竞争性更新申请是我们长期研究肝细胞生长因子（HGF）及其c-met受体在正常和患病肾脏中的作用和机制的延续。本申请前期的研究表明，HGF及其c-met受体可能在成人肾脏小管存活、修复和再生以及维持肾小管细胞分化状态中发挥重要作用。在本继续申请中，我们提出创建条件性敲除小鼠模型，其中c-met受体基因在肾脏中的肾小管上皮细胞中特异性地被无效突变。通过使用这个模型系统，我们将测试的假设，即HGF/c-met是一个主要的信号系统，在许多生理和病理生理环境中的肾细胞存活和分化的控制。这些研究将在三个具体目标下完成。在目标1中， 研究细胞存活对c-met受体细胞丰度的依赖性;并阐明c-met受体对肾小管上皮细胞的HGF非依赖性细胞保护的新机制。在目标2中，我们将研究肾小管特异性c-met条件性敲除小鼠在正常条件下和急性肾损伤后肾小管细胞死亡和肾功能的速率和程度。目的3：研究和比较正常条件下肾小管特异性c-met基因敲除小鼠和单侧输尿管梗阻所致慢性肾损伤小鼠的肾小管上皮细胞表型。这些研究将为了解正常和疾病条件下控制肾小管细胞存活，修复和分化的机制提供基础和重要的见解。最终，这些研究可能导致开发新的策略，通过操纵HGF/c-met信号系统的活动来改变人类肾脏疾病的过程。