Because of current, limited options for treating overactive bladder (OAB) or lower urinary tractsymptoms (LUTS), there is a great demand for the development of new treatment strategy. Inthis application, the following key aims utilize unique and innovative expertise, available atWilliam Beaumont Hospital and University of Pittsburgh to develop new therapeutic options forOAB and detrusor overactivity (DO) by especiallytargeting bladder afferent hyperexcitability, which has been proposed as one of the importantmechanisms underlying OAB, using rats with spinal cord injury (SCI). Sequence-specific gene-silencing mechanism is a promising approach for developing therapeutics agent based onrational gene-based drug design. In the current proposal, we propose to use this approach forsilencing nerve growth factor (NGF) gene locally in the bladder. Local inhibition of NGF gene inbladder akin to antisense eye drops for corneal angiogenesis can avoid the safety concernsnoted with systemic anti-NGF therapy from monoclonal human NGF antibodies (tanezumab)such as paresthesia, hypoesthesia and arthralgia. By comparing the pharmacology of NGFantisense administered via different routes, we propose to investigate the contribution of NGFderived from urothelium on afferent hyperexcitability leading to DO in SCI animals.Secondly, we will also test the hypothesis of OAB pathology triggered by changes in voltage-gated sodium and potassium channels, increased cytokines expression/release as well asmuscarinic receptors, and such changes are mediated by excessive NGF expression in bladder.The proposed experiments will use antisense to elucidate whether NGF inhibition couldnormalize changes in muscarinic and ion channel mechanisms contributing to afferenthyperexcitability resulting in DO/OAB. We will study the changes in the local muscariniccholinergic mechanism underlying DO, including altered sensitivity to various antimuscarinicagents. This mechanism is important to investigate because there is increasing evidence thatnon-neural acetylcholine (ACh) released from the urothelium during stretch can activatemuscarinic receptors, leading to modulation of afferent pathways during the micturition reflex,and that increased ACh levels in the bladder can induce OAB mediated by the local effects onmuscarinic receptors in the urothelium/suburothelium. The long-term objectives of the researchprogram are to establish new and effective therapeutic targets and/or interventions strategies forthe treatment of OAB.

Public Health Relevance

Overactive bladder (OAB) inducing urgency and urinary frequency increasingly interfere with the quality of life, and are sometimes difficult to treat. This project seeks to clarify the neurogenic mechanisms inducing bladder overactivity using the animal model of OAB in order to provide a translational foundation for the development of new therapeutic modalities such as nerve growth factor (NGF) antisense treatment for this difficult condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK088836-02
Application #
8432297
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2011-09-01
Project End
2015-07-31
Budget Start
2012-04-20
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$380,798
Indirect Cost
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Kawamorita, Naoki; Yoshikawa, Satoru; Kashyap, Mahendra et al. (2016) Liposome Based Intravesical Therapy Targeting Nerve Growth Factor Ameliorates Bladder Hypersensitivity in Rats with Experimental Colitis. J Urol 195:1920-6
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