The apical surface of mammalian urothelium is almost completely covered by rigid-looking urothelial plaques consisting of 16 nm uroplakin particles that are hexagonally packed into two-dimensional crystals. Highly purified urothelial plaques are comprised of four major uroplakins (UP), i.e., uroplakin Ia (27 kDa), Ib (28 kDa), II (15 kDa) and III (47 kDa). The two tetraspanin members UPIa and UPIb interact preferentially with the two single transmembrane-domained uroplakins II and III, respectively, forming two uroplakin pairs consisting of UPIa/II and UPIb/III. During the last grant period, we genetically ablated mouse genes encoding for uroplakins II and III. Mice deficient in these two major urothelial differentiation products have a grossly abnormal urothelium lacking typical umbrella cells; have abnormally small urothelial plaques; and suffer from vesicoureteral reflux, hydronephrosis and, in some cases, neonatal death. These results indicate that uroplakins are integral subunits of the urothelial plaques which contribute to the permeability barrier function, and that urothelial defects may play a role in certain urinary tract diseases. Little is known, however, about how uroplakin defects may affect urothelial and bladder function as a whole, how uroplakins interact with cytoplasmic and other membrane-associated proteins, and how surface-accessible are the uroplakin receptors to the uropathogenic bacteria. The proposed studies in this Project will attempt to answer some of these questions, by studying how the ablation of uroptakin genes affects the permeability barrier and micturition functions of the bladder (Aim 1); how uroplakins interact with some cytoplasmic proteins that may play a role in mediating uroplaldn:cytosketetal interaction and signal transduction (Aim 2); and how accessible uroplakin molecules are on the apical surface of urothelial umbrella cells, and whether there are other uroplakin-associated cell surface proteins that may be related to the urotheliat 'glycocalyx' coating that has been hypothesized to play a key role in several bladder diseases (Aim 3). Results from this Project will shed light on the structure, function and regulation of urothelial plaques, and will have major implications on the molecular etiology and pathogenesis of several important bladder diseases including interstitial cystitis, urinary tract infection and bladder cancer formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK052206-10
Application #
7662280
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
10
Fiscal Year
2008
Total Cost
$283,012
Indirect Cost
Name
New York University
Department
Type
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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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