(Taken directly from the application) The apical surface of mammalian urothelium is covered with numerous rigid-looking plaques consisting of two dimensional crystals of 16-nm protein particles. These plaques, also known as the asymmetric unit membranes, are the structural hallmark of urothelial terminal differentiation and are presumed to play a central functional role in enabling the urothelium to perform its physiological function, i.e., to serve as a highly impermeable and flexible barrier. However, how precisely the urothelial plaques accomplish this is not at all clear. It is also unclear how the genes encoding the protein subunits of the urothelial plaques are regulated so that they are expressed in a urothelium-specific and differentiation-dependent fashion. Answers to these questions are crucially important for us to understand how urothelium functions in normal physiological conditions, and how abnormalities in uroplakin structure and gene regulation may give rise to certain bladder diseases. Therefore the long term goal of this project is to define more precisely the biological functions of urothelial plaques, and to better understand in molecular terms how the uroplakin genes are regulated. Towards these goals, we will perform two series of experiments focusing on the genetic abrogation and regulation of selected uroplakin genes: (1) To disrupt some of the uroplakin genes by homologous recombination in order to generate uroplakin-deficient mice and to assess the in vivo functions of urothelial plaques; and (2) To dissect the regulatory sequences of some of the uroplakin genes in order to determine the roles of various cis-motifs in the tissue-specific and differentiation-dependent expression of these genes. The results of these studies will lead to a better understanding of the function and regulation of uroplakin genes, and may give raise to animal models of human bladder diseases.
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