A Genetic Model of Urogenital Development & Obstruction

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DESCRIPTION (provided by applicant): Diseases of the urinary bladder affect an estimated 35 million people in the United States, with end-stage renal failure in children alone estimated to cost over $15 billion dollars annually. Despite the prevalence of bladder disease, little is currently known regarding the mechanisms controlling these processes. We have identified a unique insertional mutant mouse model that develops in utero megabladder resulting in variable hydroureteronephrosis and chronic renal failure secondary to obstructive uropathy. These animals, designated mgb for megabladder, possess a primary defect in bladder smooth muscle development that is apparent by embryonic day 15, and whose functional outcome appears gender-influenced. Clarifying the precise developmental and functional defects found in mgb mice and determining the genetic locus responsible for these abnormalities will provide valuable information regarding the molecular mechanisms controlling urogenital development and disease. The long-term objectives of this project are to gain a better understanding of the complex molecular pathways that control normal bladder development and pathogenesis, In Specific Aim 1 we propose to complete the characterization of the mgb phenotype using both histological and immunohistochemical techniques. In Specific Aim 2, we intend to identify the genetic locus responsible for the mgb phenotype using an overlapping, multifaceted approach that includes cytogenetic characterization of the transgene insertion site, identification of genomic break points, expression analysis of candidate genes, and phenotype rescue by reverse transgenesis. Finally, in Specific Aim 3, we will perform morphometric analysis, in vitro cystometry and ultrasound to characterize the functional state of mgb mice, and correlate this to the clinical state of the animals using urine output and serum chemistry. Completion of these studies will significantly enhance our understanding of normal bladder development and pathogenesis, and permit the formulation and evaluation of therapeutic strategies in the future.