PROJECT 1 - Spinal cord injury (SCI) leads to detrusor-sphincter-dyssynergia, bladder overdistension and dramatic remodeling of the bladder wall and neurons that innervate the organ. These contribute to the development of detrusor overactivity. Project 1 will focus on the role of afferent sensitization, remodeling and increased neuropeptide release as well as interstitial cell (IC) hyperplasia following thoracic level (T8-T9) spinal cord transection (i.e., SCI) in mice. In addition, we will test potential therapeutic agents that target afferent nerves, IC and nerve growth factor (NGF). There are three specific aims.
Aim 1 will measure afferent sprouting, sensitization and neuropeptide release which, our data suggest, is more predominant in the trigone. This will be achieved through the use of our unique optical mapping approaches and bladder sheet preparations combined with afferent nerve recordings/stimulation. We will inject,pseudorabies virus, genetically encoded with the fluorescent Ca2+ indicator,GCaMP4, into the dorsal root ganglia to selectively label bladder afferent nerves.
Aim 2 will examine the role of IC as pacemakers that drive spontaneous contractions that may contribute to detrusor overactivity following SCI. We hypothesize that nitric oxide released from the urothelium, which normally attenuates IC firing, is insufficient due to SCI-induced IC hyperplasia. This theory will be tested in bladder wall-cross sections utilizing optical mapping with high- resolution CMOS cameras that can differentiate the individual cell layers within the bladder wall.
Aim 3 will investigate the therapeutic benefits of botulinum neurotoxin serotype-A, p3-adrenergic receptor agonists, PDE-5 inhibitors and nen/e growth factor antibodies (NGF-AB). These agents have been shown to have beneficial effects on the bladder and we propose to determine if this is through direct actions on afferent nerves and/or IC. We believe that the combination of unique approaches, preparations and interactions with the other projects will help clarify the mechanisms responsible for SCI-induced dysfunction and uncover new therapies for its treatment.

Public Health Relevance

It is very important to develop a better understanding of the mechanisms that drive afferent sensitization and interstitial cell overactivity following spinal cord injury, as these may lead to new therapeutic approaches and optimization of existing ones to decrease detrusor overactivity and treat urinary incontinence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK093424-02
Application #
8723173
Study Section
Special Emphasis Panel (ZDK1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Tyagi, Pradeep; Kashyap, Mahendra; Yoshimura, Naoki et al. (2016) Past, Present, and Future of Chemodenervation With Botulinum Toxin in the Treatment of OAB. J Urol :
Kadekawa, Katsumi; Yoshimura, Naoki; Majima, Tsuyoshi et al. (2016) Characterization of bladder and external urethral activity in mice with or without spinal cord injury--a comparison study with rats. Am J Physiol Regul Integr Comp Physiol 310:R752-8
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
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