Acquired and congenital obstruction of the vas deferens, ureter and renal vasculature, lead to alterations in reproductive and kidney function. This renewal for an O'Brian urology Research Center is focused on the cellular and molecular mechanisms underlying neonatal or pre-pubertal obstruction of the testis, epididymidis, and kidney. Four projects by established senior investigators are proposed. Project 1 investigates the altered phenotype of renal tubular epithelial cells (RTE) after neonatal ureteral obstruction. Deranged cellular polarity, apoptosis and crosstalk between RTE and interstitial fibroblasts will be examined in a ureteral and single nephron obstruction models offering insight into pediatric hydronephrotic disorders. Project 2 investigates the regulatory mechanisms and genomic events leading to the development of obstructed renal vasculature, especially with regard to the role of angiotensin in preserving normal renal vascular morphology. Phenotypic changes, vascular remodeling, and the lineage of cells participating in vessel growth in angiotensin deficient mice will be investigated. Project 3 studies the effect of vasal obstruction on epithelial function both proximal to (epididymis) and distal to (prostate) the site of obstruction. Cellular biochemistry and synthetic events will be studies. Reversibility of changes in protein synthesis and luminal secretion following relief of obstruction will be studied in both epididymis and prostate. These data will provide insight into persistent infertility after vasovasotomy and determine if vasectomy alters prostate growth or function. Project 4 explores the effects of pre-pubertal and adult obstruction on seminiferous epithelium, induction of antisperm antibodies, and characterization of sperm autoantigens. These findings may identify new and important sperm antigens involved in reproductive tract alterations (fertility). Investigators in this P50 share common themes, mechanisms and methods of investigation. These projects represent a refinement and focusing of efforts, building on strengths in reproductive biology and pediatric nephrology at the University of Virginia.
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