instaictions): PROJECT 2 - Evidence supports a role for urinary bladder urothelial cells in the transduction of sensory events. Though studies have focussed on the effects of spinal cord injury (SCI) on innervation and smooth muscle, little is known regarding changes in urothelial barrier and signaling properties. We have identified a number of abnormalities in the urothelium (UT) of SCI bladders including alterations in barrier function and a hyperplasia as well as a heightened sensitivity to mechanical and chemical stimuli. Changes to the urothelial barrier occur as early as a few hours following SCI and may be mediated in part by an interaction with bladder nerves (directly or indirectly via urothelial-cell interactions). In contrast, the regenerative process (occurs within the first few weeks following SCI) takes place when bladder nerves are quiescent, suggesting a role for additional factors (including trophic factors). These processes are not mutually exclusive, but interact in a complex manner culminating in altered UT structure and function that can impact on bladder function. The goals of this project are to evaluate and understand mechanisms that underiie both the eariy and delayed changes in the UT that occur following SCI.
Aim #1 will evaluate the mechanisms by which neurotransmitters promote acute barrier disruption by measuring transepithelial resistance and permeability. We will also examine whether pelvic nerve stimulation mimics the acute changes of SCI on UT barrier function.
Aim #2 will evaluate mechanisms underlying delayed responses of the UT following SCI. We will evaluate whether chronic overdistension of the bladder plays a role in urothelial structure and proliferative function and the involvement of NGF by use of chronic antibody treatment in SCI animals.
Aim #3 will continue to examine the impact of chronic SCI on UT function by use of in-line isolated cells, bladder sheets and cross-sections of intact bladder and optical imaging to examine transmitters that may influence UT-cell communication. The Ca2+ sensing protein, GCaMP4, will also be used to measure afferent-UT dynamics in a physiologically relevant context. This use of different experimental approaches will help us elucidate mechanisms underlying changes in cellular responses in SCI.

Public Health Relevance

The bladder urothelium, in addition to its barrier function, plays an important role in the transduction of sensory events. Understanding how the urothelial barrier is disrupted by SCI then repaired and how changes in epithelial function impacts on sensory signaling is of major physiological importance (potentially providing therapeutic targets to alleviate the downstream effects of nerve injuries).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
United States
Zip Code
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:

Showing the most recent 10 out of 48 publications