Congenital obstructive nephropathy is the principal cause of pediatric renal failure. The molecular and cellular lesions leading to congenital obstruction, however, are still largely undetermined. We have shown that the absence of calcineurin in the developing urinary tract mesenchyme, in the Pax3Cre Cnb1 mutants we generated, led to congenital obstructive nephropathy resembling Ureteropelvic Junction (UPJ) obstruction in humans. Our study has demonstrated a clear requirement for calcineurin in urinary tract development and provided us with materials and knowledge to further investigate the indispensable signaling events involved and the etiology of congenital obstructive nephropathy. We propose to first study the interactions between calcineurin and other signaling pathways known to be involved in urinary tract development. This will test the hypothesis that calcineurin is an indispensable signaling transducer for urinary tract development. This will also effectively connect our observations to the existing knowledge in this field and will provide a more comprehensive explanation, at the molecular and cellular level, for the pathogenesis of the congenital obstructive nephropathy. Then, we will develop primary and immortalized cell lines carrying the Cnb1 deletion to determine the effects of calcineurin inactivation in cellular behavior and signaling to test the hypothesis that calcineurin is required for interpreting various extracellular signals in cells of the urinary tract. We will also use genomic/proteomic approaches and molecular genetic methods to identify factors downstream of calcineurin in urinary tract development. Furthermore, we will complement the Pax3Cre-Cnb1 study with Cnb1 deletion in the ureteric bud (UB) derivatives to test the hypothesis that calcineurin has additional indispensable in vivo function in the UB and in the epithelial-mesenchymal interactions during urinary tract development. We will use these mutants to further analyze the interactions of the relevant signaling pathways in vivo. Results from the proposed studies will provide mechanistic insights into the function of calcineurin in normal and abnormal development of the urinary tract and the etiology of congenital obstructive nephropathy.
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