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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK052206-13
Application #
8333912
Study Section
Special Emphasis Panel (ZDK1-GRB-S (M2))
Program Officer
Mullins, Christopher V
Project Start
1999-03-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
13
Fiscal Year
2012
Total Cost
$1,514,400
Indirect Cost
$602,943
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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
Mathai, John C; Zhou, Enhua H; Yu, Weiqun et al. (2014) Hypercompliant apical membranes of bladder umbrella cells. Biophys J 107:1273-9
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
Zhou, Ge; Liang, Feng-Xia; Romih, Rok et al. (2012) MAL facilitates the incorporation of exocytic uroplakin-delivering vesicles into the apical membrane of urothelial umbrella cells. Mol Biol Cell 23:1354-66
Schnegelsberg, Birthe; Sun, Tung-Tien; Cain, Gary et al. (2010) Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol 298:R534-47
Guo, Xuemei; Tu, Liyu; Gumper, Iwona et al. (2009) Involvement of vps33a in the fusion of uroplakin-degrading multivesicular bodies with lysosomes. Traffic 10:1350-61
Wang, Huaibin; Min, Guangwei; Glockshuber, Rudi et al. (2009) Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction. J Mol Biol 392:352-61
Garcia-Espana, Antonio; Mares, Roso; Sun, Tung-Tien et al. (2009) Intron evolution: testing hypotheses of intron evolution using the phylogenomics of tetraspanins. PLoS One 4:e4680
He, Feng; Mo, Lan; Zheng, Xiao-Yong et al. (2009) Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis. Cancer Res 69:9413-21
Wu, Xue-Ru; Kong, Xiang-Peng; Pellicer, Angel et al. (2009) Uroplakins in urothelial biology, function, and disease. Kidney Int 75:1153-65

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