Axons provide long-range communication in the nervous system. Regeneration of axons in the injured spinal cord brings the potential to reconnect the caudal spinal cord to rostral brain stem and cerebrum and restore sensory and motor function. Significant advances have been made in the field of neural 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 spinal cord and interventions aimed at overcoming the inhibitory microenvironment can modulate intraaxonal signaling events that converge on the local protein synthesis machinery and this contributes to axonal growth and maturation. We will 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 III (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 regiens 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.

Public Health Relevance

Axons have the ability to generate their own proteins needed for regeneration, but it is not clear if this occurs in the spinal cord or if neural repair strategies developed for spinal cord injury target this intra-axonal signaling mechanism. We will determine how growth supportive environments for spinal cord regeneration and training regimens that can improve functional recovery impact on axonal signal transduction and axon regrowth.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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Neurological Sciences and Disorders A (NSD-A)
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Jakeman, Lyn B
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Drexel University
Anatomy/Cell Biology
Schools of Medicine
United States
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Spruance, Victoria M; Zholudeva, Lyandysha V; Hormigo, Kristiina M et al. (2018) Integration of Transplanted Neural Precursors with the Injured Cervical Spinal Cord. J Neurotrauma 35:1781-1799
Zholudeva, Lyandysha V; Qiang, Liang; Marchenko, Vitaliy et al. (2018) The Neuroplastic and Therapeutic Potential of Spinal Interneurons in the Injured Spinal Cord. Trends Neurosci 41:625-639
Bezdudnaya, Tatiana; Hormigo, Kristiina M; Marchenko, Vitaliy et al. (2018) Spontaneous respiratory plasticity following unilateral high cervical spinal cord injury in behaving rats. Exp Neurol 305:56-65
Kar, Amar N; Lee, Seung Joon; Twiss, Jeffery L (2018) Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease. Neuroscientist 24:111-129
Jin, Ying; Shumsky, Jed S; Fischer, Itzhak (2018) Axonal regeneration of different tracts following transplants of human glial restricted progenitors into the injured spinal cord in rats. Brain Res 1686:101-112
Zholudeva, Lyandysha V; Iyer, Nisha; Qiang, Liang et al. (2018) Transplantation of Neural Progenitors and V2a Interneurons after Spinal Cord Injury. J Neurotrauma 35:2883-2903
Chhaya, Soha J; Quiros-Molina, Daniel; Tamashiro-Orrego, Alessandra D et al. (2018) Exercise-Induced Changes to the Macrophage Response in the Dorsal Root Ganglia Prevent Neuropathic Pain after Spinal Cord Injury. J Neurotrauma :
Sahoo, Pabitra K; Smith, Deanna S; Perrone-Bizzozero, Nora et al. (2018) Axonal mRNA transport and translation at a glance. J Cell Sci 131:
Lane, Michael A; Lepore, Angelo C; Fischer, Itzhak (2017) Improving the therapeutic efficacy of neural progenitor cell transplantation following spinal cord injury. Expert Rev Neurother 17:433-440
Nair, Jayakrishnan; Bezdudnaya, Tatiana; Zholudeva, Lyandysha V et al. (2017) Histological identification of phrenic afferent projections to the spinal cord. Respir Physiol Neurobiol 236:57-68

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