Spinal cord injury (SCI) currently affects approximately 250,000 people in the U.S., with more than 10,000 new cases occurring each year. Currently, there is no cure for SCI. This study seeks to establish appropriate therapeutic interventions in a chronic SCI situation to support neuroanatomical and neurophysiological recovery. Work from the current funding period further defined the neuroprotective role of glial cell line-derived neurotrophic factor (GDNF) after an acute injury, the use of matrix-degrading enzymes to modify a spinal cord injury site, and the response of chronically injured neurons to neurotrophic factor (NTF) therapy after a second injury. This proposal will build upon this work and progress into new territory by addressing the significance of modulating an SCI site before applying strategies designed to accelerate axonal regrowth. We will also attempt to reduce some negative aspects of the neuronal response to injury by treating an acute injury with NTFs to heighten the regenerative effort of these neurons at chronic stages injury.
The Specific Aims address the hypotheses that 1) degradation of the extracellular matrix prior to NTF treatment will increase axonal regeneration in the injured spinal cord, 2) acute neuroprotective therapy will enhance strategies for neuroregeneration in a chronic injury situation, and 3) regeneration enhanced by combined acute and chronic interventions can be characterized by changes in expression of regeneration-associated genes and/or activation of specific signaling pathways.
Aim I will use an established cervical SCI-peripheral nerve (PN) graft model to test whether modulation of the extracellular matrix of the injured spinal cord prior to use of NTFs enhances axonal outgrowth from a PN graft and whether matrix-degrading enzymes effectively treat an established glial scar.
Aim II examines acute neuroprotective treatment with GDNF to promote long-term survival and regeneration of chronically injured neurons.
In Aim III, possible mechanisms underlying GDNF-enhanced regeneration after chronic injury will be examined by studying the expression of regeneration-associated genes and activated signaling pathways using laser microdissection, quantitative RT-PCR, and Western blot procedures. Overall, these experiments will provide fundamental information about cellular and molecular aspects of the neuronal and non-neuronal responses to long-term injury that will be instrumental in designing intervening therapies to repair the chronically injured spinal cord.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS026380-23
Application #
7798012
Study Section
Special Emphasis Panel (ZRG1-CNNT (01))
Program Officer
Owens, David F
Project Start
1988-08-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
23
Fiscal Year
2010
Total Cost
$411,149
Indirect Cost
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sandrow-Feinberg, Harra R; Houlé, John D (2015) Exercise after spinal cord injury as an agent for neuroprotection, regeneration and rehabilitation. Brain Res 1619:12-21
Detloff, Megan Ryan; Smith, Evan J; Quiros Molina, Daniel et al. (2014) Acute exercise prevents the development of neuropathic pain and the sprouting of non-peptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury. Exp Neurol 255:38-48
Detloff, Megan Ryan; Wade Jr, Rodel E; Houlé, John D (2013) Chronic at- and below-level pain after moderate unilateral cervical spinal cord contusion in rats. J Neurotrauma 30:884-90
Houle, John D; Cote, Marie-Pascale (2013) Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann N Y Acad Sci 1279:154-63
Tom, Veronica J; Sandrow-Feinberg, Harra R; Miller, Kassi et al. (2013) Exogenous BDNF enhances the integration of chronically injured axons that regenerate through a peripheral nerve grafted into a chondroitinase-treated spinal cord injury site. Exp Neurol 239:91-100
Liu, Ting; Houle, John D; Xu, Jinye et al. (2012) Nanofibrous collagen nerve conduits for spinal cord repair. Tissue Eng Part A 18:1057-66
Cote, Marie-Pascale; Amin, Arthi A; Tom, Veronica J et al. (2011) Peripheral nerve grafts support regeneration after spinal cord injury. Neurotherapeutics 8:294-303
Sandrow-Feinberg, Harra R; Zhukareva, Victoria; Santi, Lauren et al. (2010) PEGylated interferon-beta modulates the acute inflammatory response and recovery when combined with forced exercise following cervical spinal contusion injury. Exp Neurol 223:439-51
Xi, Dong; Keeler, Benjamin; Zhang, Wentong et al. (2009) NMDA receptor subunit expression in GABAergic interneurons in the prefrontal cortex: application of laser microdissection technique. J Neurosci Methods 176:172-81
Houle, John D; Amin, Arthi; Cote, Marie-Pascale et al. (2009) Combining peripheral nerve grafting and matrix modulation to repair the injured rat spinal cord. J Vis Exp :

Showing the most recent 10 out of 38 publications