The George M. O'Brien Urology Research Center at the University of Pennsylvania is an inter-institutional, multidisciplinary program that focuses its research on the molecular mechanisms underlying smooth muscle dysfunction in partial urinary bladder outlet obstruction (PBOO). The Center has three key elements: 1) the laboratories of five principal investigators and Co-PIs who bring expertise in molecular biology, cellular biology, biochemistry, physiology, pharmacology, and pathology; 2) an administrative core (Core A) to provide administrative oversight, quality control of projects, coordination of the research and interactions in the Urology Center; and 3) a bladder tissue core (Core B) to serve as a resource for smooth muscle tissue from animal models (rabbits and mice) for PBOO as well as human bladder tissue from surgical specimens. The projects are, 1: Extracellular Matrix Changes in Response to Obstruction (Macarak), 2: Effect of Extracellular Matrix and Stretch on the Expression of Smooth Muscle Phenotype during Detrusor Smooth Muscle Remodeling (DiSanto), 3: Cellular and Molecular Basis of Detrusor Contractility and Bladder Dysfunction in obstruction-induced detrusor remodeling (Chacko), and 4 A&B: Mechanism for the regulation of cross-bridge cycling and force generation and maintenance in bladder remodeling following outlet obstruction (Moreland & Barsotti). In addition, we have two Cores, a Bladder Tissue Core (Zderic), and an Administrative Core (Chacko & Wein), and two Pilot & Feasibility Projects. These are 1) Dimunition of Detrusor Hypertrophy in Outlet Obstruction by Inhibition of Calcineurine Pathway with Cyclosporin (Zderic) and (2) Phospholipase Activation During Bladder Obstruction (LaBelle). The new proposal will determine which signal transduction pathways lead to Ca2+-sensitization, actin-myosin interaction, crossbridge cycling, and how they are altered in the remodeling detrusors. Furthermore, it will help to establish which changes are reversible upon removal of the obstruction, and which molecular events are not reversible in the bladders that continue to be dysfunctional even after reversal of the obstruction. Data from these studies would help elucidate the cellular/molecular basis for the alteration of detrusor contractility following PBOO, to identify molecular markers that can be used to determine which obstructed bladder is remodeled beyond a point that contractile dysfunction is irreversible, and to target molecular steps for developing therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK052620-10
Application #
7284154
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (M1))
Program Officer
Hoshizaki, Deborah K
Project Start
1998-09-18
Project End
2008-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
10
Fiscal Year
2007
Total Cost
$842,267
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hypolite, Joseph A; Chang, Shaohua; Wein, Alan J et al. (2015) Protein kinase C modulates frequency of micturition and non-voiding contractions in the urinary bladder via neuronal and myogenic mechanisms. BMC Urol 15:34
Long, C J; Butler, S; Fesi, J et al. (2014) Genetic or pharmacologic disruption of the calcineurin-nuclear factor of activated T-cells axis prevents social stress-induced voiding dysfunction in a murine model. J Pediatr Urol 10:598-604
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
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
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
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
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
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

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