Over-expression of Neurotrophin-3 (NT-3) in lumbar motoneurons induces axons to grow from the contralateral corticospinal tract (CST) towards the source of NT-3 in rats but only if the CST ipsilateral to the transduced motoneurons is lesioned and if the NT-3 over-expression is coincident with the time of lesion. If NT-3 over-expression is delayed 4m after the lesion there is no axonal growth suggesting that at least one factor associated with the acute phase of the CST injury is involved. If the rats with acute CST lesions were immunosuppressed axonal growth in response to NT-3 is blocked. When the experiment was repeated in athymic nude (AN) rats there was no axonal growth in response to NT-3. If the immune response is re-activated in chronically lesioned rats with systemic lipopolysaccharide (LPS) NT-3 will induce axonal growth. This is the first demonstration of inducing axonal growth with neurotrophins in achronically lesioned CNS. These observations suggest that NT-3-induced axonal growth requires processes associated with immune-mediated wound healing;specifically activated T- cells. The goals of this project are to identify the factor or factors associated with immune-mediated wound healing and test them in conjunction with NT-3 in our model of chronic spinal cord injury.
The specific aims are to: (1) verify the role of T-cells in NT-3-induced axonal growth, identify the T-cell subtype responsible, (2) determine the role of microglial activation in this process, and (3) identify genes and proteins differentially expressed in conditions that support NT-3 induced axonal growth compared to those that do not using qPCR and protein expression using multiplex array immunoassays in AN rats. Our results show that neuroplasticity can be induced in the chronically injured spinal cord distal to the lesion site. This neuroplasticity is likely induced by the presence of NT-3 and a factor, or factors, associated with immune-mediated wound healing. If the identity of the factor(s) associated with the acute injury can be identified then it may be possible to recapitulate the acute environment in patients with chronic spinal cord injuries to induce neuroplasticity in spared axonal tracts. Two-thirds of spinal cord injury patients have incomplete cord transections so strategies to enhance the function of the remaining connections by enabling the inherent plasticity of the CNS may provide improvement in function of patients with chronic spinal cord injury.

Public Health Relevance

The Armed Forces'activities in both peace- and war-time present situations for catastrophic neural injuries. It is improbable with today's biomedical technologies that the injured CNS can be repaired by inducing the regeneration of severed axons. However, it is not improbable that some function may be gained by the CNS's innate ability to mount a compensatory reorganization through collateral sprouting of spared axons. This proposal is based upon our recent discoveries that immune-related processes are involved in axonal growth after injuryand that reactivating these immune processes will enable axonal growth in the chronic injured CNS. This work addresses the basic biology of recovery from SCI with the belief that this knowledge may be used to develop new, or refine existing, strategies to help repair these neural injuries. It seeks to determine the underlying mechanism of neurotrophin-induced axonal regeneration after SCI in order to develop means to treat chronic CNS injuries.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Spinal Cord Injury & Regenerative Medicine (RRD0)
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Michael E Debakey VA Medical Center
United States
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