The development of organs and their function is governed by the differentiation and patterning of cells through the coordinated expression of specific genes. This competitive renewal for an O'Brien Urology Research Center is focused on the genetic, molecular and cellular events that regulate genitourinary (GU) tract development. Four projects by established senior scientists and two pilots by junior investigators spanning two clinical and one basic science department with a ten-year record of productive collaboration are proposed. Project 1 (Gomez) examines the role of a novel kidney-specific gene in proximal tubular cell maturation and function. Whether sequence elements in the promoter region of this gene determine organ and cell specificity will be investigated. Project 2 (Chevalier) will study the mediators of both salutary and injurious effects in a newly developed model of neonatal partial ureteral obstruction. A translational research component will search for urinary markers for obstructive nephropathy. Early detection may enhance recovery from obstructive renal injury. Pilot 1 (Roth) will dovetail on Project 2 by examining the embryonic origin and lineage of ureteral smooth muscle. It will be determined whether clonal expansion versus synchronous migration of differing cell types contributes to ureteral expansion and will offer insight into hydronephrotic disorders. Project 3 (Turner) investigates the developmental and regulatory (androgenic), compensatory (vasectomy), and genomic events leading to the synthesis of natural antibacterial peptides, including defensins, in the GU tract. Project 4 (Flickinger) examines development and novel consequences of epididymal segmentation involving sonic hedgehog pathway genes. Pilot 2 (Lysiak) investigates the role of caspase 2 and downstream pro-apoptotic members of the Bcl-2 family in establishing the number of germ cells in the testis. Investigators in this P50 share common themes and study similar mechanisms yet direct attention on different organs within the GU tract. The proposed investigations will advance the development of novel diagnostic tests and therapies for disorders ranging from renal insufficiency to male infertility building on strengths in reproductive and cell biology, urology and pediatric nephrology at the University of Virginia.
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