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.
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