Spinal cord injury (SCI) is one of the most damaging, immobilizing, and irreversible injuries for a human being to survive. T8 complete transection results in interruption of ascending and descending pathways. A major consequence of complete transection SCI is the so-called neurogenic bladder, which results in a lack of coordinated activities between the bladder and the external urethral sphincter (EUS). One potential repair strategy that could allow for the resumption of supraspinal control of bladder activity utilizes peripheral nerve grafting (PNG) to provide a favorable environment for axonal regeneration and remyelination in order to bridge the lesion gap. However, use of the PNG alone allows for only limited numbers of regenerated nerve fibers to reach targets at the distal end of spinal cord. One member of the family of extracellular matrix molecules, chondroitin sulfate proteoglycans (CSPG), creates an unfavorable environment for nerve regeneration, sprouting and synaptic plasticity beyond the graft. CSPGs in the forming scar also block the regenerated nerve fibers through the lesion site. Recent studies have demonstrated that the enzyme chondroitinase ABC (ChABC) by cleaving the inhibitory sugar side chains on CSPGs has the ability to overcome the inhibition of axon growth from scar-associated matrix. Therefore, the ultimate goal of this application is to construct multi- PNG bridges across the lesion to promote long distance regeneration but also allow regenerated nerve fibers to exit the bridge through degradation of inhibitory extracellular matrix at the PNG/spinal cord interface. We will test the hypothesis that the combination of a PNG + acidic fibroblast growth factor and ChABC application can enhance nerve regeneration and promote bladder function recovery in rats with T8 complete transection more efficiently than the various components of the therapy used alone. We will characterize, quantify and compare any improving micturition patterns (frequency and volume of each micturition), urodynamic characteristics, and detrouser / EUS dyssynergia among the various groups of animals. In addition, we also will test the hypothesis that restored bladder function with a PNG+aFGF+ ChABC treatment is correlated with and/or dependent upon the regeneration of long tract fibers after T8 complete transection. Finally, spinal cord re-transection will be used to determine whether improved micturition patterns and other urodynamic improvements will degrade or disappear after lesioning the PNG bridge. This multipartite strategy has the potential to lead to an unprecedented amount of functional plasticity/regeneration and bladder recovery after SCI.

Public Health Relevance

There are more than 200,000 individuals living with a spinal cord injury (SCI) in the United States alone. Individuals with SCI have a significant economic burden of healthcare and dependent living. Restoring partial function can result in greater independence, thereby improving quality of life and reducing this burden. In particular, the restoration of bladder function is a high priority of SCI individuals to improve their quality of life. Reconnecting of damaged spinal cord through nerve regeneration is a potential treatment to regain bladder control after SCI. The current proposal is aimed at combing nerve regeneration strategies to uncover the underlying mechanisms and to test the effectiveness of a novel therapeutic approach for this important function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069765-04
Application #
8464814
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Ludwig, Kip A
Project Start
2010-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$324,789
Indirect Cost
$117,917
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Lee, Yu-Shang; Danandeh, Andalib; Baratta, Janie et al. (2013) Neurotrophic factors rescue basal forebrain cholinergic neurons and improve performance on a spatial learning test. Exp Neurol 249:178-86
Jiang, Hai-Hong; Kokiko-Cochran, Olga N; Li, Kevin et al. (2013) Bladder dysfunction changes from underactive to overactive after experimental traumatic brain injury. Exp Neurol 240:57-63
Lee, Yu-Shang; Lin, Ching-Yi; Jiang, Hai-Hong et al. (2013) Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J Neurosci 33:10591-606
Lin, Ching-Yi; Lee, Yu-Shang; Lin, Vernon W et al. (2012) Fibronectin inhibits chronic pain development after spinal cord injury. J Neurotrauma 29:589-99