Over the past eleven years, we have worked as a Program Project team consisting of four investigators with diverse expertise in the areas of epithelial cell biology, structural biology and membrane trafficking to study, in several closely interrelated projects, the cell and molecular biology and diseases of mammalian urothelium. Our research focuses on, as a central and unifying theme, a group of integral membrane proteins called uroplakins that represent major differentiation markers of mammalian urothelium. During the last granting period (2004-2009), our team has demonstrated that abrogation of uroplakins in transgenic mice resulted in compromised urothelial barrier function and overactive bladder;that defects in Rab27 and Vps33a lead to a depletion of fusiform vesicles and an accumulation of multivesicular bodies, respectively, thus establishing their involvement in uroplakin trafficking;that FimH can induce transmembrane conformational changes in the uroplakin receptor complex thus providing a novel mechanism for the bacterium-induced host cell changes; and that distinctive molecular alterations in genetically engineered mice underlie the two pathways of urothelial tumorigenesis. 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 progress advancing the urothelial biology field. During the next five-year grant period, we will continue to work as a team to ask the following questions: What are the roles of uroplakins in the stabilization, enlargement and repair of the urothelial apical surface (Project 1)? What are the roles of molecular machineries including MAL and Rab27b in regulating uroplakin trafficking (Project 2)? What is the structure of uroplakins and how does the uroplakin complex anchor into an underlying cytoskeleton (Project 3)? And what are the roles of individual uroplakins and their subdomains in the uroplakin receptor complex in mediating the bacterial binding-induced signals in host umbrella cells (Project 4)? Results from this highly collaborative and synergetic team effort will lead to a better understanding of urothelial function, and have implications on a number of important urological problems including bladder outlet obstruction and urinary tract infection.

Public Health Relevance

The apical surface of urinary bladder urothelium plays a key role in urothelial function. Our team will study, in a highly collaborative and synergistic marmer, how this surface membrane is made, maintained and repaired, and how the binding of the uropathogenic bacteria to urothelial surface can lead to bacterial invasion and recurrent infection.

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-S (M2))
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Mullins, Christopher V
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New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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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:
Mathai, John C; Zhou, Enhua H; Yu, Weiqun et al. (2014) Hypercompliant apical membranes of bladder umbrella cells. Biophys J 107:1273-9
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

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