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.

Public Health Relevance

Axons have the ability to generate their own proteins needed for regeneration, but 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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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Drexel University
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Ollivier-Lanvin, Karen; Fischer, Itzhak; Tom, Veronica et al. (2015) Either brain-derived neurotrophic factor or neurotrophin-3 only neurotrophin-producing grafts promote locomotor recovery in untrained spinalized cats. Neurorehabil Neural Repair 29:90-100
Lee, Seung Joon; Kalinski, Ashley L; Twiss, Jeffery L (2014) Awakening the stalled axon - surprises in CSPG gradients. Exp Neurol 254:12-7
Jin, Ying; Bouyer, Julien; Haas, Christopher et al. (2014) Behavioral and anatomical consequences of repetitive mild thoracic spinal cord contusion injury in the rat. Exp Neurol 257:57-69
Singh, Anita; Krisa, Laura; Frederick, Kelly L et al. (2014) Forelimb locomotor rating scale for behavioral assessment of recovery after unilateral cervical spinal cord injury in rats. J Neurosci Methods 226:124-31
Graziano, Alessandro; Foffani, Guglielmo; Knudsen, Eric B et al. (2013) Passive exercise of the hind limbs after complete thoracic transection of the spinal cord promotes cortical reorganization. PLoS One 8:e54350
Houle, John D; Cote, Marie-Pascale (2013) Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann N Y Acad Sci 1279:154-63
Haas, Christopher; Fischer, Itzhak (2013) Human astrocytes derived from glial restricted progenitors support regeneration of the injured spinal cord. J Neurotrauma 30:1035-52
Liu, Gang; Detloff, Megan Ryan; Miller, Kassi N et al. (2012) Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Exp Neurol 233:447-56
Keeler, Benjamin E; Liu, Gang; Siegfried, Rachel N et al. (2012) Acute and prolonged hindlimb exercise elicits different gene expression in motoneurons than sensory neurons after spinal cord injury. Brain Res 1438:8-21
Ketschek, A R; Haas, C; Gallo, G et al. (2012) The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition. Exp Neurol 235:627-37

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