The George M. O'Brien Urology Research Center at the University of Pennsylvania entitled "Bladder Wall Remodeling in LUTS" has three key elements: (1) the laboratories of five principal investigators and the Co-PIs that bring expertise in molecular biology, cellular biology, neuroscience, biochemistry, physiology, pharmacology, and pathology;(2) an Administrative Core (Core A) to provide administrative and fiscal oversight, quality control for the research within individual projects and coordination of the research and interactions in the Center;(3) a Bladder Tissue Core (Core B) to serve as a resource for smooth muscle tissue of the LUTS from rabbits, rats, and mice (normal and obstructed bladders and urethra). In addition, we have Educational and Enrichment and Pilot and Feasibility (P&F) programs to attract young investigators and established investigators in working in other biomedical areas to urologic research. The four projects are: (1) Social-stress-induced urinary dysfunction: A model of dysfunctional voiding from Rita J. Valentino;(2) Bladder wall remodeling following alteration of urothelial structure from Pamela S. Howard (in collaboration with Dr. Tung-Tien Sun of NYU);(3) Mechanism for obstruction-induced detrusor remodeling: role of hypoxia and stretch from Samuel K. Chacko;and (4) Extracellular matrix changes response to obstruction from Edward J. Macarak. The two P&F projects are: (1) Urethral function in females: A Role for estrogen from Shaohua Chang;and (2) The effect of PBOO and estrogen on detrusor smooth muscle in female rabbits from Gina M. Northington. The focus of the O?Brien Program is to elucidate the mechanism for social stress- and PBOO-induced functional and structural changes in the bladder wall leading to LUTS. These studies will provide a useful model for dysfunctional voiding in children and elucidate the molecular basis for urinary dysfunction in menopausal women and aging men with BPH-induced PBOO. A better understanding of the basic mechanisms for alteration of the structure and function of the bladder wall and urethra in LUTS would help to develop therapeutic strategies targeting altered molecular events that cause altered function in lower urinary tract.

Public Health Relevance

This proposal addresses the cellular/molecular mechanisms that cause stress- and obstruction-induced lower urinary tract symptoms (LUTS). LUTS are a major burden for ageing men and women. LUTS cause micturition problems which adversely affect patient quality of life, sleep, increase patient anxiety about the disease, and adversely affect patient mobility, leisure, daily and sexual activities. In many cases, LUTS is a major indication for surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK052620-15
Application #
8333896
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O1))
Program Officer
Hoshizaki, Deborah K
Project Start
1998-09-18
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
15
Fiscal Year
2012
Total Cost
$859,020
Indirect Cost
$250,346
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Marx, James O; Basha, Maureen E; Mohanan, Sunish et al. (2014) Effects of Rho-kinase inhibition on myosin light chain phosphorylation and obstruction-induced detrusor overactivity. Int J Urol 21:319-24
Boopathi, Ettickan; Gomes, Cristiano; Zderic, Stephen A et al. (2014) Mechanical stretch upregulates proteins involved in Ca2+ sensitization in urinary bladder smooth muscle hypertrophy. Am J Physiol Cell Physiol 307:C542-53
Eto, Masumi; Kirkbride, Jason A; Chugh, Rishika et al. (2013) Nuclear localization of CPI-17, a protein phosphatase-1 inhibitor protein, affects histone H3 phosphorylation and corresponds to proliferation of cancer and smooth muscle cells. Biochem Biophys Res Commun 434:137-42
Deng, Maoxian; Boopathi, Ettickan; Hypolite, Joseph A et al. (2013) Amino acid mutations in the caldesmon COOH-terminal functional domain increase force generation in bladder smooth muscle. Am J Physiol Renal Physiol 305:F1455-65
Boopathi, Ettickan; Hypolite, Joseph A; Zderic, Stephen A et al. (2013) GATA-6 and NF-ýýB activate CPI-17 gene transcription and regulate Ca2+ sensitization of smooth muscle contraction. Mol Cell Biol 33:1085-102
Hypolite, Joseph A; Lei, Qi; Chang, Shaohua et al. (2013) Spontaneous and evoked contractions are regulated by PKC-mediated signaling in detrusor smooth muscle: involvement of BK channels. Am J Physiol Renal Physiol 304:F451-62
Wood, Susan K; McFadden, Kile; Griffin, Tagan et al. (2013) A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats. Am J Physiol Regul Integr Comp Physiol 304:R940-50
Basha, Maureen E; Chang, Shaohua; Burrows, Lara J et al. (2013) Effect of estrogen on molecular and functional characteristics of the rodent vaginal muscularis. J Sex Med 10:1219-30
Wei, Wenjie; Howard, Pamela S; Macarak, Edward J (2013) Recombinant insulin-like growth factor-1 activates satellite cells in the mouse urethral rhabdosphincter. BMC Urol 13:62
Speich, John E; Southern, Jordan B; Henderson, Sheree et al. (2012) Adjustable passive stiffness in mouse bladder: regulated by Rho kinase and elevated following partial bladder outlet obstruction. Am J Physiol Renal Physiol 302:F967-76

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