INTRODUCTION ? The goals of this program are to characterize lower urinary tract (LUT) dysfunction due to spinal cord injury and to test new therapies. Effects of spinal! cord injury are multifaceted involving changes in the spinal cord, peripheral neurons and different cell types in the bladder and urethra leading to detrusorsphincter- dyssynergia, urothelial cell hyperplasia, interstitial cell pacemaker activity, afferent nerve sensitization and smooth muscle cell hypertrophy. Therapies to be tested include botulinum neurotoxin serotype A, |33-adrenergic receptor agonists, PDE-5 inhibitrors, and nerve growth factor and brain-derived neurotrophic factor antibodies. Optical mapping techniques we developed are extremely effective in studying LUT and are a key link between projects. These approaches utilize unique mouse and rat preparations including spinal cord slices, bladder-urethra sheets, sheets with spinal nerves, wall cross-sections and 'inline'primary urothelial, neuronal, interstitial and smooth muscle cells. GCaMP4 encoded viral vectors will be used to label sensory nerves innervating the bladder and sensory nerves and motoneurons in the spinal cord controlling the bladder and urethral sphincter. The program Pis and core Directors have extensive expertise in urologic research and optical mapping. Anthony Kanai, project 1 and imaging core co-director, is an expert in afferent nerve, urothelial and interstitial cell interactions and was first to use optical mapping to study the LUT. Lori Birder, project 2, is an expert in urothelial cell pathophysiology and was first to demonstrate their neuronal-like properties. Naoki Yoshimura, project 3, is an expert in the pathophysiology of sensory neurons and was first to demonstrate changes in ion channel expression in DRG neurons as a mechanism for bladder afferent sensitization. William de Groat, project 4 and animal core director, is an expert on the autonomic pathophysiology of the LUT and was first to show the role of C-fiber afferents in bladder overactivity. Guy Salama, imaging core co-director, is an expert in optical mapping and was first to develop methods to simultaneously record action potentials and Ca2+ transients. We are confident that our experience and unique approaches will lead to a very interactive and fruitful program.

Public Health Relevance

Altered neurogenic and myogenic regulation is the underlying cause for a number of LUT disorders including those related to spinal cord injury. This highly collaborative program will greatly enhance our understanding of LUT dysfunctions following spinal cord injury and potentially lead to new therapeutic options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK093424-01A1
Application #
8415613
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (O1))
Program Officer
Mullins, Christopher V
Project Start
2013-08-20
Project End
2018-07-31
Budget Start
2013-08-20
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,605,744
Indirect Cost
$530,214
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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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