The long-term objectives of this study are to define the regenerative capabilities of chronically injured neurons associated with a spinal cord injury and to determine whether neurotransplantation approaches can lead to structural and functional repair of the traumatized spinal cord.
The specific aims of this application are focused on identification of intrinsic neuronal properties that may influence either the capacity for regeneration or the ability to respond to exogenous neurotrophic factors (NTFs) with an enhanced regenerative effort. Additional experiments are designed to evaluate the role of specific non-neuronal cells (i.e. macrophages) in the initiation and early guidance of axonal regeneration and to examine the functional activity associated with the structural integration of regrowing axons with the host spinal cord.
Aim 1 of this proposal will utilize a combination of NTF treatment with a peripheral nerve (PN) graft apposed to the injured cervical spinal cord to test whether the regenerative response of chronically injured supraspinal neurons can be enhanced.
The second aim will use a similar injury/ transplantation model to evaluate immediate early gene expression in a chronic injury condition, during the regenerative response exhibited by some supraspinal neurons and after NTF treatment to enhance regeneration by other neurons. Immunocytochemical detection of Jun protein within neurons retrogradely labeled via a PN graft will determine whether up- regulation of cjun is a necessary step in the regenerative response. In the third Aim, experiments to promote the association of macrophages with an intraspinal nitrocellulose implant co-grafted with fetal spinal cord (FSC) tissue will determine the role of these non-neuronal cells in fostering regeneration from neurons involved in a spinal cord injury. Electrophysiological techniques will be applied in Aim IV to identify functional integration of regenerated axons with neurons of the host spinal cord. Efforts to detect synaptic activity will utilize FSC tissue transplants or PN grafts as conduits for guidance of axonal growth across a spinal cord lesion. These experiments will provide valuable information about molecular, cellular and functional aspects of axonal regeneration associated with a long term spinal cord injury and will help in the design of possible combinations of surgical, trophic factor or genetic intervention to promote spinal cord repair.
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