Grants and Contracts Details
Description
Glial cell line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor-beta (TGF-beta) family, is wIdely expressed in the developing and adult central nervous system(CNS). Limited knowledge is available for its role in the repair of spinal cord injury (SCI). We hypothesized that GDNF may have neurotrophic and/or neuroprotective actions for regeneration of propriospinal and supraspinal axons as well as for modification of the glial environment that facilitates axonal growth. Preliminary results using spinal cord hemisection and Schwann cell (SC)-seeded mini-channel implantation demonstrate that GDNF promotes robust axonal regeneration through transplants. In addition to increased axonal regeneration, combined treatment using both GDNF and SCs increased myelin formation, and reduced cystic cavity formation. Thus, GDNF may playa novel therapeutic role in the regeneration and recovery of function after SCI. The laboratory of George M. Smith (the Co-PI) has examined the effects of overexpressing of several trophic factors (NGF, FGF2, GDNF, BDNF, and NT -3) on regeneration of dorsal root ganglion axons using 2nd generation recombinant adenoviruses. Further, the Dr. Christopher B. Shields (Co-PI) and his colleagues have developed a highly reproducible laceration device (Vibra-1rnife) allowing stereotaxic incision of the spinal cord (vibra-lesion) without causing mechanical compression or stretching of tissues that results from conventional lesions created by micro-scissors, knives, or wire loops. When combined with a dural repair procedure (suture or duraplasty), corticospinal axonal die-back is prevented, and connective scar tissue invasion and cystic cavity formation are markedly reduced. The goal of this proposal is to combine the strength ofthese three laboratories in a joint effort to investigate whether GDNF can promote axonal regeneration of several specific propriospinal and supraspinal pathways that contribute to the hindlimb locomotion. We will test the central hypothesis that a preformed growth-promoting
pathway promotes axons of a particular tract to regenerate across the lesion and, more importantly, grow back into the host spinal cord environment to reestablish connections with appropriate neuronal targets. This hypothesis wi1l be tested using a combination of techniques. First, axonal growth across the lesion win be accomplished by grafting SCs that over-express GDNF into the site of injury. Second, recombinant adenoviruses encoding GDNF will be injected into the distal host spinal cord to create a growth-supportive pathway for further axonal elongation into the distal cord. Third, functional recovery after anatomical regeneration wiU be tested using a battery of behavioral and electrophysiological measures. Lastly, accompanyig in vivo and in vitro experiments will be conducted to address mechanisms underlying GDNF-mediated axonal growth, myelm formation, and modification of graft-host interfaces.
Status | Finished |
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Effective start/end date | 7/15/03 → 4/30/06 |
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