Abnormalities in urothelium are believed to play a major role in several important urological disorders including interstitial cystitis and various neoplasms. Relatively little is known, however, about the molecular bases of these diseases. The long term goal of this project is to use molecular biologic and transgenic mouse techniques to dissect some of these disease processes. In this study, we will focus on a group of newly discovered genes encoding several integral membrane proteins called uroplakins (UP). As the major differentiation products of urothelium, uroplakins form the asymmetrical unit membrane plaques that cover the apical urothelial surface, and most likely play an important role in stabilizing and strengthening the luminal surface thus preventing it from rupturing during bladder distension. We will study the tissue-specificity of the 5'- upstream sequences of several human and mouse UP genes, and will use some of these promoters for targeting molecules of interest for expression in the urothelia of transgenic mice. The urothelia of some of these transgenic animals will harbor well-defined molecular defects including truncated or mutated uroplakins; others will express various growth factors and oncogenes. We anticipate that the pathological changes in the bladders of some of these animals will mimic certain aspects of IC or other human bladder disorders. Such transgenics will provide excellent model systems for studying the molecular basis of bladder diseases, and will enhance our knowledge on the regulation of urothelial growth and differentiation. Towards these goals, we will (i) isolate and characterize several human and mouse UP genes; (ii) analyze the promoter activities of these genes in transgenic mice; (iii) target the bladder-specific expression of mutated uroplakins, growth factors and oncogenes; and (iv) study the possible involvement of UP defects in interstitial cystitis and other human urological diseases.
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