Effects of the SCI Microenvironment on Intra-axonal Signaling

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Axons provide long-range communication in the nervous system. Regeneration of axons in the injured spina! cord brings the potential to reconnect the caudal spinal cord to rostra! brain stem and cerebrum and restore sensory and motor function. Significant advances have been made in the field of neura! repair that hold promise for restoring function in spinal cord injury, particularly when interventions can be combined to target multiple repair mechanisms. The studies proposed in this project will explore the intracellular mechanisms underlying improved functional recovery in spinal cord injury interventions, focusing on novel interactions in the axonal compartment. We will test the hypothesis that the microenvironment of the injured spina! cord and interventions aimed at overcoming the inhibitory microenvironment can modulate intra- axonal signaling events that converge on the local protein synthesis machinery and this contributes to axonal growth and maturation. We wil! test this hypothesis with two specific aims that bring together expertise of the principal investigator in axonal growth and intra-axonal signaling with expertise from Project 1 (Houle) in regenerative therapies for spinal cord injury and Project II (Fischer) in progenitor cell therapies for spinal cord injury. The first aim of this project asks if exercise/training regimens that have been shown to improve recovery from spinal cord injury regulate axonal growth potential through post-transcriptional mechanisms. Both overall and intra-axonal translational control mechanisms will be tested using primary neuronal cultures and peripheral nerve grafting into the transected spinal cord. The second aim will ask if precursor cells used for spinal cord injury can directly modulate intra-axonal signaling to regulate the intrinsic growth potential and maturation of axons through axonal mRNA transport and translational control mechanisms. We will integrate these data with Project II to address mRNA translation in host axons as they interact with grafted precursor cells in SCI. The overall objective of these experiments is to uncover mechanisms underlying enhanced axonal growth and signaling that can be used to rationally fine tune future neural repair strategies.