Regulaton of Urothelial Growth

Summary

Principal Investigator: Tung Tien Sun
Abstract: The luminal surface of the entire lower urinary tract including renal pelvis, ureter, bladder and proximal urethra is lined by a cell type described in standard textbooks as the transitional epithelium or urothelium, which is characterized by a highly specialized apical cell surface covered by rigid-looking urothelial plaques consisting of hexagonally packed 16 nm uroplakin particles. It has been suggested that urothelial defects can result in a loss of the permeability barrier function allowing the penetration of some urine irritants into the bladder wall thus causing pain in interstitial cystitis. In addition, it is generally assumed that urothelial cells lining the different portions of the urinary tract are the same; hence conclusions derived from studying cells of one region should be applicable to all urothelial cells. However, urothelia of renal pelvis/ureter/trigone are known to have a different embryological origin than urothelial cells of other sites, and there are indications that urothelium is biochemically heterogeneous. In this project, we will (i) determine whether the urothelia that cover renal pelvis, ureter, bladder, and proximal urethra actually consist of several distinct cell lineages by analyzing the relative contributions of intrinsic divergence vs. extrinsic modulation to urothelial phenotypes, and (ii) identify the stem cells in various urothelial compartments using cell kinetic, cell culture and stem cell transplantation techniques. These proposed studies can yield important information because if urothelium indeed can be separated into several distinct subpopulations belonging to different cell lineages, one needs to re-examine the validity of some earlier studies in which urothelial cells from different parts of the urinary tract were used interchangeably. Since stem cells are the preferred targets of carcinogens, gene therapy, and they are particularly suited for tissue engineering and tissue reconstitution, our studies can have practical implications on the source of urothelial cells for tissue engineering of various parts of the urinary tract, the cellular origin of in vivo urothelial wound healing following the surgical removal of the bladder, the possible involvement of urothelial cells in interstitial cystitis and in site-specific variations in bacterium: urothelium interactions, and the cellular origin of various urothelial tumors.
Funding Period: 2003-09-30 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. pmc Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement
    Feng Xia Liang
    Epithelial Biology Unit, The Ronald O Perelman Department of Dermatology
    J Cell Biol 171:835-44. 2005
  7. ncbi Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implications
    Stanley J Miller
    Department of Dermatology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
    Biochim Biophys Acta 1756:25-52. 2005
  8. pmc Assembly of urothelial plaques: tetraspanin function in membrane protein trafficking
    Chih Chi Andrew Hu
    Epithelial Biology Unit, The Ronald O Perelman Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA
    Mol Biol Cell 16:3937-50. 2005
  9. ncbi A survivin gene signature predicts aggressive tumor behavior
    Whitney Salz
    Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    Cancer Res 65:3531-4. 2005
  10. ncbi Urothelial umbrella cells of human ureter are heterogeneous with respect to their uroplakin composition: different degrees of urothelial maturity in ureter and bladder?
    Ina Riedel
    Institute of Pathology, Philipp University, D 35033 Marburg, Germany
    Eur J Cell Biol 84:393-405. 2005

Scientific Experts

  • TUNG-TIEN H SUN
  • Stanley J Miller
  • Xue ru Wu
  • Feng Xia Liang
  • Ge Zhou
  • Fang Ming Deng
  • Steve J Hodges
  • Hong Ying Huang
  • Ellen Shapiro
  • Jose L Luque-Garcia
  • Antonio Garcia-Espana
  • Liyu Tu
  • Gert Kreibich
  • Chih Chi Andrew Hu
  • Ina Riedel
  • Whitney Salz
  • Doug Case
  • Karl Erik Andersson
  • Pete Santago
  • Chanda Turner
  • Tamer AbouShwareb
  • George J Christ
  • Herbert Lepor
  • Shahrokh F Shariat
  • Jer Tsong Hsieh
  • Raheela Ashfaq
  • Yair Lotan
  • Pei Jung Chung
  • Jun Yu
  • Thomas A Neubert
  • Angel Pellicer
  • Xiaoqian Zhao
  • Rob DeSalle
  • Andy Lee
  • Solange Baptiste
  • Chih Hang Anthony Tang
  • Dario C Altieri
  • Dan Eisenberg
  • Michaela Hergt
  • Jessica Zhou
  • Maarten C Bosland
  • Hongying Huang
  • Roland Moll
  • Rok Romih
  • David S Garlick
  • Robert M Weiss
  • Janet Plescia

Detail Information

Publications10

  1. 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...
  2. 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...
  3. 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...
  4. 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...
  5. 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...
  6. pmc Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement
    Feng Xia Liang
    Epithelial Biology Unit, The Ronald O Perelman Department of Dermatology
    J Cell Biol 171:835-44. 2005
    ....
  7. ncbi Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implications
    Stanley J Miller
    Department of Dermatology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
    Biochim Biophys Acta 1756:25-52. 2005
    ....
  8. pmc Assembly of urothelial plaques: tetraspanin function in membrane protein trafficking
    Chih Chi Andrew Hu
    Epithelial Biology Unit, The Ronald O Perelman Department of Dermatology, New York University School of Medicine, New York, NY 10016, USA
    Mol Biol Cell 16:3937-50. 2005
    ....
  9. ncbi A survivin gene signature predicts aggressive tumor behavior
    Whitney Salz
    Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
    Cancer Res 65:3531-4. 2005
    ..Detection of survivin or its associated gene signature may provide an early biomarker of aggressive tumor behavior before the appearance of tissue abnormalities...
  10. ncbi Urothelial umbrella cells of human ureter are heterogeneous with respect to their uroplakin composition: different degrees of urothelial maturity in ureter and bladder?
    Ina Riedel
    Institute of Pathology, Philipp University, D 35033 Marburg, Germany
    Eur J Cell Biol 84:393-405. 2005
    ..Additional studies are needed to distinguish these two possibilities and to elucidate the physiological and pathological significance of the observed urothelial and uroplakin heterogeneity...