Project 3 of our Program Project is entitled """"""""lon Channels in Afferent Sensitization and Detrusor Overactivity"""""""" (Project Director: Naoki Yoshimura, Department of Urology). The following key aims will utilize unique and innovative expertise, available in our institutions, to understand the pathophysiology of detrusor overactivity (DO) and detrusor sphincter dyssynergia (DSD), especially by targeting afferent hyperexcitability, which has been proposed as one of the important mechanisms underiying lower unnary tract dysfunction in chronic spinal cord injury (SCI). First, we will study the correlated changes in bladder activity (i.e., DO) and the expression and functional properties of K""""""""^ ion channels after SCI as we have previously found that altered expression of voltage-gated K* channels is one of the key events for the induction of C-fiber hyperexcitability resulting in bladder overactivity. Secondly, we will investigate changes in the K^ and Ca^* ion channel mechanisms in pudendal afferent pathways innervating the urethra containing external urethral sphincter (EUS), and their correlation with urethral hyperactivity (i.e., DSD) after SCI as there are no previous studies that examined the SCI-induced changes in functional properties of pudendal afferent neurons innervating the urethra. Lastly, we will investigate the roles of nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) and p38 MAPK signaling in neuroplasticity of bladder and urethral afferent pathways that underlies SCI-induced DO and DSD. We will also utilize the small-interfenng RNA technique to identify molecular correlates in K* ion channel subunits that induce bladder and urethral afferent hyperexcitability. The long-term objectives of the research program are to establish new and effective therapeutic targets and/or interventions strategies for the treatment of urological problems in spinal cord disorders. There is significant synergy especially with Projects 1 and 4, which will respectively examine peripheral afferent remodeling and spinal mechanisms controlling EUS function. Project 3 also maximizes the uses of the resources of Animal and Optical Imaging Cores.

Public Health Relevance

Following spinal cord injury, increased excitability of bladder and urethral afferents lead to overactivity. Determining the ion channel mechanisms involved and preventing changes in their expression by anti-growth factor treatment could lead to a new method to prevent/treat LUT dysfunction.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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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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