EXCEED THE SPACE PROVIDED. Glomerulosclerosis is the final common pathway of the many diverse etiologies of renal failure during childhood. In this grant we will focus on transgenic mouse models in which glomerular defects are observed, and we will propose how further studies of these models will elucidate the molecular basis for glomerular damage and dysfunction. The study of glomerular development in our laboratory was initiated when gene targeting experiments performed several years ago by the Principal Investigator showed that the Wtl and a3 integrin genes has a crucial role in kidney development [1, 2]. In the case of the alpha3 integrin gene it was immediately apparent that a3bl integrin was a key protein required to assemble podocyte foot processes. Loss of the Wtl gene led to a block in the earliest stages of kidney development, not allowing study of its role in glomerular development. However, studies of humans with either the Deny-Drash or Frasier Syndromes has demonstrated an important role for Wtl in glomerular function [3-5]. In this grant we present preliminary data demonstrating that a mouse model in which to study Wtl in glomerular function has been derived, and we propose ways to extend this model to further understand how Wtl acts to maintain normal glomerular function.
The specific aims of this grant are to: (1) Establish a system to achieve inducible podocyte-specific expression of WT1 transgenes; (2) Conditionally mutate the Wtl gene in podocytes; and (3) Conditionally mutate the alpha3 integrin gene in podocytes. PERFORMANCE SITE ========================================Section End===========================================
