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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University of Pittsburgh
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Kullmann, F Aura; Beckel, Jonathan M; McDonnell, Bronagh et al. (2018) Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice. Naunyn Schmiedebergs Arch Pharmacol 391:1191-1202
Zabbarova, Irina V; Ikeda, Youko; Carder, Evan J et al. (2018) Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. Neurourol Urodyn 37:2452-2461
Shimizu, Nobutaka; Wada, Naoki; Shimizu, Takahiro et al. (2018) Effects of nerve growth factor neutralization on TRP channel expression in laser-captured bladder afferent neurons in mice with spinal cord injury. Neurosci Lett 683:100-103
Ryu, Jae Cheon; Tooke, Katharine; Malley, Susan E et al. (2018) Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest 128:1772-1786
Wada, Naoki; Shimizu, Takahiro; Shimizu, Nobutaka et al. (2018) The effect of neutralization of nerve growth factor (NGF) on bladder and urethral dysfunction in mice with spinal cord injury. Neurourol Urodyn :
Shimizu, Nobutaka; Doyal, Mark F; Goins, William F et al. (2018) Corrigendum to 'Morphological Changes in Different Populations of Bladder Afferent Neurons Detected by Herpes Simplex Virus (HSV) Vectors with Cell-type-specific Promoters in Mice with Spinal Cord Injury' [Neuroscience 364 (2017) 190-201]. Neuroscience 381:161
Beckel, Jonathan M; de Groat, William C (2018) The effect of the electrophilic fatty acid nitro-oleic acid on TRP channel function in sensory neurons. Nitric Oxide :
Ikeda, Youko; Zabbarova, Irina V; Birder, Lori A et al. (2018) Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice. Neurourol Urodyn 37:2441-2451
Shimizu, Takahiro; Majima, Tsuyoshi; Suzuki, Takahisa et al. (2018) Nerve growth factor-dependent hyperexcitability of capsaicin-sensitive bladder afferent neurones in mice with spinal cord injury. Exp Physiol 103:896-904
Kullmann, F A; Chang, H H; Gauthier, C et al. (2018) Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing. Acta Physiol (Oxf) 222:

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