During the past four and half years (since March 1, 1999), we have worked closely as a team consisting of five investigators with diverse expertise in the areas of epithelial cell biology, structural biology, membrane trafficking, and cancer biology to study, in four closely interrelated projects, the cell and molecular biology and diseases of mammalian urothelium. This Program Project focuses on, as a central theme, a group of integral membrane proteins called uroplakins that represent major differentiation markers of mammalian urothelium. During the last (first) granting period, our team has made several major advances including the knockout of uroplakin II and III genes elucidating the biological functions of uroplakin and yielding mouse models of vesicoureteral reflux; the demonstration that uroplakin heterodimer formation in ER is an early step of AUM assembly; the identification of Rab27b as a urothelium-enriched GTPase that may play a role in targeting uroplakin vesicles to the apical surface; the identification of uroplakin Ia as the receptor for typelfimbriated E. coli causing urinary tract infection; the localization of the uroplakin Ia receptor on the 6 inner subdomains of the 16 nm uroplakin particle; the visualization of mouse AUM by cryo-EM at 10 A resolution thus providing a structural basis for the permeability barrier function of urothelial plaques; and the generation of several well-characterized transgenic mice expressing specific oncogenes in their urothelia allowing a systematic study of the pathways of bladder cancer formation. Our team has therefore functioned well in pursuing biologically important problems related to urothelial growth, differentiation and diseases; in having synergetic interactions and extensive collaborations; in effectively sharing resources; and in having made significant progresses. During the next five-year grant period, we will continue to work as a team to pursue the following aims: What is the pathophysiological consequences of uroplakin ablation and how do urothelial plaques interact with other cytosolic and membrane proteins (Project 1)? What are the roles of different uroplakin subdomains in plaque assembly, and how are the uroplakin vesicles delivered and targeted to the urothelial apical surface (Project 2)? How do the individual uroplakins assemble into the 16 nm particle and whether these particles undergo conformational changes in respond to bacterial binding (Project 3)? What kind of oncogenic changes underline the various pathways of bladder tumorigenesis (Project 4)?
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