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)?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-7 (M2))
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Mullins, Christopher V
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New York University
Schools of Medicine
New York
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Chicote, Javier U; DeSalle, Rob; Segarra, José et al. (2017) The Tetraspanin-Associated Uroplakins Family (UPK2/3) Is Evolutionarily Related to PTPRQ, a Phosphotyrosine Phosphatase Receptor. PLoS One 12:e0170196
Norsworthy, Allison N; Pearson, Melanie M (2017) From Catheter to Kidney Stone: The Uropathogenic Lifestyle of Proteus mirabilis. Trends Microbiol 25:304-315
Wankel, Bret; Ouyang, Jiangyong; Guo, Xuemei et al. (2016) Sequential and compartmentalized action of Rabs, SNAREs, and MAL in the apical delivery of fusiform vesicles in urothelial umbrella cells. Mol Biol Cell 27:1621-34
Schaffer, Jessica N; Norsworthy, Allison N; Sun, Tung-Tien et al. (2016) Proteus mirabilis fimbriae- and urease-dependent clusters assemble in an extracellular niche to initiate bladder stone formation. Proc Natl Acad Sci U S A 113:4494-9
Kisiela, Dagmara I; Avagyan, Hovhannes; Friend, Della et al. (2015) Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic E. coli. PLoS Pathog 11:e1004857
Liu, Yan; Mémet, Sylvie; Saban, Ricardo et al. (2015) Dual ligand/receptor interactions activate urothelial defenses against uropathogenic E. coli. Sci Rep 5:16234
Hickling, Duane R; Sun, Tung-Tien; Wu, Xue-Ru (2015) Anatomy and Physiology of the Urinary Tract: Relation to Host Defense and Microbial Infection. Microbiol Spectr 3:
Vieira, Neide; Deng, Fang-Ming; Liang, Feng-Xia et al. (2014) SNX31: a novel sorting nexin associated with the uroplakin-degrading multivesicular bodies in terminally differentiated urothelial cells. PLoS One 9:e99644
Desalle, Rob; Chicote, Javier U; Sun, Tung-Tien et al. (2014) Generation of divergent uroplakin tetraspanins and their partners during vertebrate evolution: identification of novel uroplakins. BMC Evol Biol 14:13
Mathai, John C; Zhou, Enhua H; Yu, Weiqun et al. (2014) Hypercompliant apical membranes of bladder umbrella cells. Biophys J 107:1273-9

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