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 #
5R01DK088836-04
Application #
8528570
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
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$304,907
Indirect Cost
$103,648
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yoshimura, Naoki; Oguchi, Tomohiko; Yokoyama, Hitoshi et al. (2014) Bladder afferent hyperexcitability in bladder pain syndrome/interstitial cystitis. Int J Urol 21 Suppl 1:18-25
Yoshimura, Naoki; Miyazato, Minoru; Kitta, Takeya et al. (2014) Central nervous targets for the treatment of bladder dysfunction. Neurourol Urodyn 33:59-66
Tyagi, Pradeep; Kashyap, Mahendra P; Kawamorita, Naoki et al. (2014) Intravesical liposome and antisense treatment for detrusor overactivity and interstitial cystitis/painful bladder syndrome. ISRN Pharmacol 2014:601653
Honda, Masashi; Yoshimura, Naoki; Kawamoto, Bunya et al. (2014) Effects of sensory neuron-specific receptor agonist on bladder function in a rat model of cystitis induced by cyclophosphamide. Int Urol Nephrol 46:1953-9
Yunoki, Takakazu; Takimoto, Koichi; Kita, Kaori et al. (2014) Differential contribution of Kv4-containing channels to A-type, voltage-gated potassium currents in somatic and visceral dorsal root ganglion neurons. J Neurophysiol 112:2492-504
Yoshimura, Naoki; Ogawa, Teruyuki; Miyazato, Minoru et al. (2014) Neural mechanisms underlying lower urinary tract dysfunction. Korean J Urol 55:81-90
Yokoyama, Hitoshi; Oguchi, Tomohiko; Goins, William F et al. (2013) Effects of herpes simplex virus vector-mediated enkephalin gene therapy on bladder overactivity and nociception. Hum Gene Ther 24:170-80
Kashyap, Mahendra; Kawamorita, Naoki; Tyagi, Vikas et al. (2013) Down-regulation of nerve growth factor expression in the bladder by antisense oligonucleotides as new treatment for overactive bladder. J Urol 190:757-64
Takahashi, Ryosuke; Yoshizawa, Tsuyoshi; Yunoki, Takakazu et al. (2013) Hyperexcitability of bladder afferent neurons associated with reduction of Kv1.4 ?-subunit in rats with spinal cord injury. J Urol 190:2296-304
Corcoran, Anthony T; Yoshimura, Naoki; Tyagi, Vikas et al. (2013) Mapping the cytokine profile of painful bladder syndrome/interstitial cystitis in human bladder and urine specimens. World J Urol 31:241-6

Showing the most recent 10 out of 16 publications