Program Project: Growth, Differentiation and Disease of Urothelium

Summary

Principal Investigator: Tung Tien Sun
Abstract: 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.
Funding Period: 1999-03-01 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc EEDA: a protein associated with an early stage of stratified epithelial differentiation
    Lijie Sun
    Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    J Cell Physiol 206:103-11. 2006
  2. pmc Characteristics of the phagocytic cup induced by uropathogenic Escherichia coli
    Huaibin Wang
    Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA
    J Histochem Cytochem 56:597-604. 2008
  3. ncbi Voiding pattern analysis as a surrogate for cystometric evaluation in uroplakin II knockout mice
    Steve J Hodges
    Wake Forest Institute of Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA
    J Urol 179:2046-51. 2008
  4. pmc Assembly of a membrane receptor complex: roles of the uroplakin II prosequence in regulating uroplakin bacterial receptor oligomerization
    Chih Chi Andrew Hu
    Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Biochem J 414:195-203. 2008
  5. pmc Intron evolution: testing hypotheses of intron evolution using the phylogenomics of tetraspanins
    Antonio Garcia-Espana
    Unitat de Recerca, Hospital Joan XXIII, Institut de Investigacio Sanitaria Rovira I Virgili IISPV, Universitat Rovira i Virgili, Tarragona, Spain
    PLoS ONE 4:e4680. 2009
  6. pmc Uroplakins in urothelial biology, function, and disease
    Xue ru Wu
    Department of Urology, New York University Langone Medical Center, New York, USA
    Kidney Int 75:1153-65. 2009
  7. ncbi Involvement of vps33a in the fusion of uroplakin-degrading multivesicular bodies with lysosomes
    Xuemei Guo
    Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA
    Traffic 10:1350-61. 2009
  8. pmc Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction
    Huaibin Wang
    Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA
    J Mol Biol 392:352-61. 2009
  9. pmc Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis
    Feng He
    Department of Urology, New York University School of Medicine, Veterans Affairs Medical Center in Manhattan, New York, NY 10010, USA
    Cancer Res 69:9413-21. 2009
  10. pmc Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function
    Birthe Schnegelsberg
    Department of Neuroscience, Roche Palo Alto, Palo Alto, California, USA
    Am J Physiol Regul Integr Comp Physiol 298:R534-47. 2010

Research Grants

  1. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
  2. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
  3. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
  4. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
  5. Vanderbilt Diabetes Research Center
    Alvin C Powers; Fiscal Year: 2013
  6. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  7. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  9. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
  10. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013

Detail Information

Publications25

  1. pmc EEDA: a protein associated with an early stage of stratified epithelial differentiation
    Lijie Sun
    Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    J Cell Physiol 206:103-11. 2006
    ..Our results indicate that EEDA is involved in the early stages of normal epithelial differentiation, and that EEDA is important for the "normal" differentiation pathway in a wide range of stratified epithelia...
  2. pmc Characteristics of the phagocytic cup induced by uropathogenic Escherichia coli
    Huaibin Wang
    Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA
    J Histochem Cytochem 56:597-604. 2008
    ..This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials...
  3. ncbi Voiding pattern analysis as a surrogate for cystometric evaluation in uroplakin II knockout mice
    Steve J Hodges
    Wake Forest Institute of Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA
    J Urol 179:2046-51. 2008
    ..We developed a simple surrogate measure of bladder function using ultraviolet visualization of urinary voiding patterns in a uroplakin II knockout mouse animal model...
  4. pmc Assembly of a membrane receptor complex: roles of the uroplakin II prosequence in regulating uroplakin bacterial receptor oligomerization
    Chih Chi Andrew Hu
    Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA
    Biochem J 414:195-203. 2008
    ..Our results indicate that proper secondary modifications of the prosequence of UPII play important roles in regulating the oligomerization and function of the UP protein complex...
  5. pmc Intron evolution: testing hypotheses of intron evolution using the phylogenomics of tetraspanins
    Antonio Garcia-Espana
    Unitat de Recerca, Hospital Joan XXIII, Institut de Investigacio Sanitaria Rovira I Virgili IISPV, Universitat Rovira i Virgili, Tarragona, Spain
    PLoS ONE 4:e4680. 2009
    ..The analysis of exon/intron gene structure in such an evolutionary broad set of genomes allowed us to identify ancestral intron structure in tetraspanins throughout the eukaryotic tree of life...
  6. pmc Uroplakins in urothelial biology, function, and disease
    Xue ru Wu
    Department of Urology, New York University Langone Medical Center, New York, USA
    Kidney Int 75:1153-65. 2009
    ..We also call attention to important areas where greater investigative efforts are warranted...
  7. ncbi Involvement of vps33a in the fusion of uroplakin-degrading multivesicular bodies with lysosomes
    Xuemei Guo
    Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA
    Traffic 10:1350-61. 2009
    ....
  8. pmc Uropathogenic E. coli adhesin-induced host cell receptor conformational changes: implications in transmembrane signaling transduction
    Huaibin Wang
    Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA
    J Mol Biol 392:352-61. 2009
    ..Our results suggest a novel pathogen-induced transmembrane signal transduction mechanism that plays a key role in the initial stages of UPEC invasion and receptor-mediated bacterial invasion in general...
  9. pmc Deficiency of pRb family proteins and p53 in invasive urothelial tumorigenesis
    Feng He
    Department of Urology, New York University School of Medicine, Veterans Affairs Medical Center in Manhattan, New York, NY 10010, USA
    Cancer Res 69:9413-21. 2009
    ....
  10. pmc Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function
    Birthe Schnegelsberg
    Department of Neuroscience, Roche Palo Alto, Palo Alto, California, USA
    Am J Physiol Regul Integr Comp Physiol 298:R534-47. 2010
    ..NGF-overexpressing mice may, therefore, provide a useful transgenic model for exploring the role of NGF in urinary bladder dysfunction...
  11. pmc MAL facilitates the incorporation of exocytic uroplakin-delivering vesicles into the apical membrane of urothelial umbrella cells
    Ge Zhou
    Department of Cell Biology, NYU Cancer Institute, NYU Langone Medical Center, New York University, New York, NY 10016, USA
    Mol Biol Cell 23:1354-66. 2012
    ....
  12. ncbi Appearance of new tetraspanin genes during vertebrate evolution
    Antonio Garcia-Espana
    Research Unit, Universitat Rovira i Virgili, Hospital Joan XXIII, Pere Virgily Institute, Tarragona 43007, Spain
    Genomics 91:326-34. 2008
    ....
  13. pmc Analysis of electroblotted proteins by mass spectrometry: protein identification after Western blotting
    Jose L Luque-Garcia
    Kimmel Center for Biology and Medicine, Skirball Institute and Department of Pharmacology
    Mol Cell Proteomics 7:308-14. 2008
    ..Finally, we demonstrate the utility of BARN for the direct identification of soluble and membrane proteins after Western blotting, obtaining comparable or better results than with in-gel digestion...
  14. pmc Atomic force microscopy of Mammalian urothelial surface
    Laurent Kreplak
    M E Müller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland
    J Mol Biol 374:365-73. 2007
    ....
  15. ncbi Distinct glycan structures of uroplakins Ia and Ib: structural basis for the selective binding of FimH adhesin to uroplakin Ia
    Bo Xie
    Mass Spectrometry Resource, Boston University School of Medicine, 670 Albany Street, Boston, MA 02118, USA
    J Biol Chem 281:14644-53. 2006
    ..Results from this study shed light on the molecular pathogenesis of urinary tract infections and may aid in the design of glyco-mimetic inhibitors for preventing and treating this disease...
  16. ncbi Altered phenotype of cultured urothelial and other stratified epithelial cells: implications for wound healing
    Tung Tien Sun
    Epithelial Biology Unit, Department of Dermatology, New York University Cancer Institute, Medical School, 550 First Ave, New York, NY 10016, USA
    Am J Physiol Renal Physiol 291:F9-21. 2006
    ..Cultured urothelial and other stratified epithelial cells provide excellent models for studying the regulation of the synthesis and assembly of differentiation products, a key cellular process during epithelial wound repair...
  17. pmc Structural basis for tetraspanin functions as revealed by the cryo-EM structure of uroplakin complexes at 6-A resolution
    Guangwei Min
    Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA
    J Cell Biol 173:975-83. 2006
    ..The rod-shaped tetraspanin structure allows it to serve as stable pilings in the lipid sea, ideal for docking partner proteins to form structural/signaling networks...
  18. ncbi Origin of the tetraspanin uroplakins and their co-evolution with associated proteins: implications for uroplakin structure and function
    Antonio Garcia-Espana
    Unitat de Recerca, University Hospital Joan XXIII, Universitat Rovira i Virgili, 46007 Tarragona, Spain
    Mol Phylogenet Evol 41:355-67. 2006
    ..The structure and function of uroplakins, which are also expressed in Xenopus kidney, oocytes and fat body, are much more versatile than hitherto appreciated...
  19. pmc Use of nitrocellulose membranes for protein characterization by matrix-assisted laser desorption/ionization mass spectrometry
    Jose L Luque-Garcia
    Department of Pharmacology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA
    Anal Chem 78:5102-8. 2006
    ..Our improved on-membrane digestion protocol greatly improves the study of soluble and, particularly strikingly, integral membrane proteins by mass spectrometry...
  20. ncbi Integrity of all four transmembrane domains of the tetraspanin uroplakin Ib is required for its exit from the ER
    Liyu Tu
    Department of Cell Biology, The Ronald O Perelman, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA
    J Cell Sci 119:5077-86. 2006
    ..Results of sedimentation analysis suggested that aggregate formation is a mechanism for ER retention...
  21. pmc Selective enrichment and fractionation of phosphopeptides from peptide mixtures by isoelectric focusing after methyl esterification
    Chong Feng Xu
    Department of Pharmacology and Skirball Institute of Biomolecular Medicine, and Department of Biochemistry, NYU School of Medicine, New York, New York 10016, USA
    Anal Chem 79:2007-14. 2007
    ..We also showed that 2,6-dihydroxy-acetophenone is superior to 2,5-dihydroxybenzoic acid as a matrix for MALDI Q-TOF MS of methylated phosphopeptides in both positive and negative ion modes...
  22. pmc Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis
    Lan Mo
    Department of Urology, New York University Cancer Institute, New York University School of Medicine, New York, New York, USA
    J Clin Invest 117:314-25. 2007
    ....
  23. pmc Persistent uroplakin expression in advanced urothelial carcinomas: implications in urothelial tumor progression and clinical outcome
    Hong Ying Huang
    Department of Urology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA
    Hum Pathol 38:1703-13. 2007
    ..Our results also suggest that UP-positive and -negative carcinomas have different clonal origins or may be derived from different cancer stem cells...
  24. pmc The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo
    Michael T Buckley
    Urology, New York University School of Medicine, New York, USA
    J Transl Med 5:49. 2007
    ....
  25. pmc Generation of divergent uroplakin tetraspanins and their partners during vertebrate evolution: identification of novel uroplakins
    Rob DeSalle
    Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, New York, USA
    BMC Evol Biol 14:13. 2014
    ....

Research Grants30

  1. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  2. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
    ..abstract_text> ..
  3. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  4. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
  5. Vanderbilt Diabetes Research Center
    Alvin C Powers; Fiscal Year: 2013
    ..Because of the VDRTC and the environment it creates, VDRTC-affiliated investigators have made important scientific contributions related to diabetes, obesity, and metabolism. ..
  6. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  7. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  9. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  10. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  11. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  12. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..