Regulaton of Urothelial Growth
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
- Voiding pattern analysis as a surrogate for cystometric evaluation in uroplakin II knockout miceSteve 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...
- Persistent uroplakin expression in advanced urothelial carcinomas: implications in urothelial tumor progression and clinical outcomeHong 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...
- Use of nitrocellulose membranes for protein characterization by matrix-assisted laser desorption/ionization mass spectrometryJose 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...
- Origin of the tetraspanin uroplakins and their co-evolution with associated proteins: implications for uroplakin structure and functionAntonio 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...
- Altered phenotype of cultured urothelial and other stratified epithelial cells: implications for wound healingTung 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...
- Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacementFeng Xia Liang
Epithelial Biology Unit, The Ronald O Perelman Department of Dermatology
J Cell Biol 171:835-44. 2005....
- Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implicationsStanley J Miller
Department of Dermatology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
Biochim Biophys Acta 1756:25-52. 2005....
- Assembly of urothelial plaques: tetraspanin function in membrane protein traffickingChih 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....
- A survivin gene signature predicts aggressive tumor behaviorWhitney 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...
- 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...