Bladder remodeling occurs as a result of diverse insults and injury to the lower urinary tract, including urethral obstruction, infection, inflammaton and neural injury, and is central to the development of fibrosis, loss of compliance and the voiding dysfunction that ensues. Despite study over several decades, the molecular signals underlying pathologic bladder remodeling remain poorly understood. Current treatments rely heavily on pharmacological modulation of the cholinergic and adrenergic axes. Although these interventions are effective for some patients, these agents only provide symptomatic relief and do not target underlying disease processes. Thus, the identification of novel pathways that actually drive pathologic remodeling is essential if fundamentally new strategies for therapy are to be developed. Evidence obtained during the current funding cycle has implicated the AP-1 and MYC transcriptional complexes as key drivers of bladder smooth muscle cell response to fibroproliferative signals, including mechanical stimulation in vitro and in vivo, and the mitogen, platelet-derived growth factor (PDGF). In the first global assessment of the PDGFR-regulated transcriptome and proteome in any organ or cell type, we used expression profiling, quantitative proteomics analysis, and state-of-the-art bioinformatics and identified MYC and JUN/AP-1 as the most significantly networked transcriptional regulators in PDGF-stimulated primary bladder smooth muscle cells (pBSMC). MYC emerged for the first time as a novel master regulator of PDGF- stimulated transcription. Upregulation of MYC and JUN/AP1, and their gene targets were confirmed in PDGF- treated pBSMC and in response to acute bladder outlet obstruction in vivo. Pharmacologic inhibition confirmed the involvement of MYC and JUN/AP-1 in regulation of pBSMC behaviors, such as proliferation and migration that contribute to pathologic remodeling. Based on these observations we hypothesize that AP-1 and MYC are key instigators of fibroproliferative remodeling in bladder smooth muscle and represent novel therapeutic targets in the setting of bladder fibrosis. This hypothesis will be tested with the following Specific Aims (1) Determine the functional significance of the MYC-centric network in bladder smooth muscle remodeling. (2) Determine the effect of pharmacologic inhibition of AP-1 on remodeling and fibrosis in the context of bladder outlet obstruction. We will employ rodent models of partial bladder outlet obstruction and spinal cord injury, together with morphological, functional and expression analyses to determine the consequences of MYC and AP-1 perturbation in vivo. At the end of the project period we will understand the biological significance of AP-1 and MYC in fibroproliferation and whether they represent `druggable' targets capable of attenuating the deleterious consequences of bladder wall remodeling.

Public Health Relevance

New findings from our group have identified the AP-1 and MYC transcriptional complexes as key drivers of fibroproliferative remodeling in bladder smooth muscle. The proposed studies will determine the biological significance of these regulatory nodes in models of physical and functional bladder outlet obstruction and will determine the effect of genetic or pharmacologic perturbation of MYC and AP-1, respectively, on tissue remodeling and bladder function. Information emerging from these studies will allow us to determine whether inhibition of AP-1 and/or MYC represent viable strategies for mitigating the deleterious effects of fibroproliferative remodeling, and to yield new knowledge that will enable the identification of additional regulatory nodes and `druggable' targets in the setting of obstructive disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077195-07
Application #
9122412
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mullins, Christopher V
Project Start
2006-12-01
Project End
2019-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
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