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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-6 (O1))
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University of Pittsburgh
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Sunagawa, Masataka; Wolf-Johnston, Amanda; Nomiya, Masanori et al. (2015) Urinary bladder mucosal responses to ischemia. World J Urol 33:275-80
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
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
Honda, Masashi; Yoshimura, Naoki; Inoue, Seiya et al. (2013) Inhibitory role of the spinal galanin system in the control of micturition. Urology 82:1188.e9-13