The major goal of this proposal is to determine the cellular and molecular mechanisms responsible for the up-regulation of extracellular matrix genes and proteins, specifically types I and III collagen, in bladder fibrosis. Congenital and acquired obstructive uropathies, as the sequelae to neurologic lesions (myelomeningocele, tethered cord syndrome) or physical alteration (posterior urethral valves, BPH) can result in fibrosis of the bladder wall. We have previously demonstrated that the terminal response is an accumulation of collagens in abnormal locations and an alteration in the type III :l collagen ratio. We have shown that angiotensin II can act through a TGF-beta1 -dependent mechanism in the up-regulation of collagens, and that this occurs through another down-stream protein factor. We will test the hypothesis that extracellular matrix changes in human bladder smooth muscle cells and fibroblasts in vitro are regulated by a TGF-beta1 via a cascade mechanism involving down-stream mediator, connective tissue growth factor CTGF. We will determine if the effect of TGF-beta1 on regulation of collagenous protein occurs via CTGF RNA and protein expression, and if the CTGF effect occurs through not only synthesis, but also involves alteration in the degradation/inhibition pathway through analysis of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). In vivo, murine partial bladder outlet obstruction studies will determine if the fibrotic response is owing to a TGF-beta and CTGF dependent mechanism, using conditional gene targeting experiments whereby the CTGF gene is ablated in smooth muscle cells, CTGF transgenic animals, and in vivo antibody inhibition experiments. We will also determine whether treatment with HMG-CoA reductase inhibitors (statins) can ameliorate the fibrotic response by inhibiting the CTGF pathway, both in in vitro and in vivo models. This research seeks to target translational therapeutic strategies to attenuate or block the fibrotic response in obstructive, and possibly inflammatory, uropathies. The statins are currently in use as cholesterol lowering agents in the general population, with side effects which have been rigorously documented. The potential use of statins would be of enormous benefit to all patients with, or having the potential to develop, bladder fibrosis, since the drug has few serious side effects and has been evaluated and approved by the FDA for other uses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK048215-13
Application #
7781324
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
1993-09-30
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
13
Fiscal Year
2010
Total Cost
$313,253
Indirect Cost
Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Wei, Wenjie; Howard, Pamela S; Kogan, Barry et al. (2012) Urinary diversion results in marked decreases in proliferation and apoptosis in fetal bladder. J Urol 188:1306-12
Wei, Wenjie; Howard, Pamela S; Zderic, Steven A et al. (2008) Beta and gamma-sarcoglycans are decreased in the detrusor smooth muscle cells of the partially obstructed rabbit bladder. J Urol 179:2052-6
Wei, Wenjie; Howard, Pamela S; Kogan, Barry et al. (2007) Altered extracellular matrix expression in the diverted fetal sheep bladder. J Urol 178:1104-7
Stevenson, Karen; Kucich, Umberto; Whitbeck, Catherine et al. (2006) Functional changes in bladder tissue from type III collagen-deficient mice. Mol Cell Biochem 283:107-14
Macarak, Edward J; Schulz, Jake; Zderic, Stephen A et al. (2006) Smooth muscle trans-membrane sarcoglycan complex in partial bladder outlet obstruction. Histochem Cell Biol 126:71-82
Howard, Pamela S; Kucich, Umberto; Coplen, Douglas E et al. (2005) Transforming growth factor-beta1-induced hypertrophy and matrix expression in human bladder smooth muscle cells. Urology 66:1349-53
He, Yuling; Macarak, Edward J; Korostoff, Jonathan M et al. (2004) Compression and tension: differential effects on matrix accumulation by periodontal ligament fibroblasts in vitro. Connect Tissue Res 45:28-39
Howard, Pamela S; Renfrow, David; Schechter, Norman M et al. (2004) Mast cell chymase is a possible mediator of neurogenic bladder fibrosis. Neurourol Urodyn 23:374-82
Matsumoto, Seiji; Kogan, Barry A; Levin, Robert M et al. (2003) Response of the fetal sheep bladder to urinary diversion. J Urol 169:735-9

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