Recent studies have indicated that combinatorial treatments that target multiple mechanisms are necessary to address the limited regenerative capacity in the adult nervous system. We have shown that chemotropic guidance by growth factor gradients, activation of cell-intrinsic regenerative programs and suitable cellular bridges at a lesion site allow for axons to extend across a lesion site in the injured spinal cord. Further, regenerated axons form ultrastructurally identified synapses with appropriate target neurons. However, several challenges that limit the relevance of current approaches remain: Regenerating axons only extend for limited distances beyond the lesion site and axons are not functional possibly due to an insufficient number of synapses or a lack of myelination.
The proposed experiments will address these limitations in 3 specific aims. We will examine spatially and temporally controlled expression of neurotrophic factors (NT-3) to enhance the distance of regeneration and target reinnervation by ascending sensory axons after adult spinal cord injury. We will further define the requirements for persistent target innervation using transient neurotrophin expression and we will examine whether localized degradation of inhibitory extracellular matrix will enhance synapse formation with target neurons. Finally, we will determine whether Schwann cell and oligodendrocyte precursor cell grafts can re-myelinate regenerating axons and augment functional connectivity and electrophysiological recovery of regenerated axons.