Because of current, limited options for treating overactive bladder (OAB) or lower urinary tract symptoms (LUTS), there is a great demand for the development of new treatment strategy. In this application, the following key aims utilize unique and innovative expertise, available at William Beaumont Hospital and University of Pittsburgh to develop new therapeutic options for OAB and detrusor overactivity (DO) by especially targeting bladder afferent hyperexcitability, which has been proposed as one of the important mechanisms underlying OAB, using rats with spinal cord injury (SCI). Sequence-specific gene-silencing mechanism is a promising approach for developing therapeutics agent based on rational gene-based drug design. In the current proposal, we propose to use this approach for silencing nerve growth factor (NGF) gene locally in the bladder. Local inhibition of NGF gene in bladder akin to antisense eye drops for corneal angiogenesis can avoid the safety concerns noted with systemic anti-NGF therapy from monoclonal human NGF antibodies (tanezumab) such as paresthesia, hypoesthesia and arthralgia. By comparing the pharmacology of NGF antisense administered via different routes, we propose to investigate the contribution of NGF derived 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 as muscarinic receptors, and such changes are mediated by excessive NGF expression in bladder. The proposed experiments will use antisense to elucidate whether NGF inhibition could normalize changes in muscarinic and ion channel mechanisms contributing to afferent hyperexcitability resulting in DO/OAB. We will study the changes in the local muscarinic cholinergic mechanism underlying DO, including altered sensitivity to various antimuscarinic agents. This mechanism is important to investigate because there is increasing evidence that non-neural acetylcholine (ACh) released from the urothelium during stretch can activate muscarinic 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 on muscarinic receptors in the urothelium/suburothelium. The long-term objectives of the research program are to establish new and effective therapeutic targets and/or interventions strategies for the 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 #
5R01DK088836-05
Application #
8706852
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Bavendam, Tamara G
Project Start
2011-09-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$308,809
Indirect Cost
$104,975
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Tyagi, Pradeep; Kadekawa, Katsumi; Kashyap, Mahendra et al. (2016) Spontaneous Recovery of Reflex Voiding Following Spinal Cord Injury Mediated by Anti-inflammatory and Neuroprotective Factors. Urology 88:57-65
Honda, Masashi; Hikita, Katsuya; Kawamoto, Bunya et al. (2016) Spinal glycine transporter-1 inhibition influences the micturition reflex in urethane-anesthetized rats. Int Urol Nephrol 48:349-54
Kashyap, Mahendra; Pore, Subrata; Yoshimura, Naoki et al. (2016) Constitutive expression Of NGF And P75(NTR) affected by bladder distension and NGF antisense treatment. Life Sci 148:93-8
Kashyap, Mahendra; Pore, Subrata; Chancellor, Michael et al. (2016) Bladder overactivity involves overexpression of MicroRNA 132 and nerve growth factor. Life Sci 167:98-104
Shimizu, Takahiro; Shimizu, Shogo; Higashi, Youichirou et al. (2016) A Stress-Related Peptide Bombesin Centrally Induces Frequent Urination through Brain Bombesin Receptor Types 1 and 2 in the Rat. J Pharmacol Exp Ther 356:693-701
Tyagi, Pradeep; Kashyap, Mahendra; Hensley, Harvey et al. (2016) Advances in intravesical therapy for urinary tract disorders. Expert Opin Drug Deliv 13:71-84
Majima, Tsuyoshi; Funahashi, Yasuhito; Takai, Shun et al. (2015) Herpes Simplex Virus Vector-Mediated Gene Delivery of Poreless TRPV1 Channels Reduces Bladder Overactivity and Nociception in Rats. Hum Gene Ther 26:734-42
Kashyap, Mahendra; Pore, Subrata; Wang, Zhou et al. (2015) Inflammasomes are important mediators of prostatic inflammation associated with BPH. J Inflamm (Lond) 12:37
Beckel, Jonathan M; Daugherty, Stephanie L; Tyagi, Pradeep et al. (2015) Pannexin 1 channels mediate the release of ATP into the lumen of the rat urinary bladder. J Physiol 593:1857-71

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