Enhancing Forelimb Recovery by Promoting Forelimb Corticospinal Tract Regeneration after Spinal Cord Injury

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The corticospinal tract (CST) is the most important voluntary motor control system in humans. Spinal cord injury (SCI) irreversibly damages the CST, which leads to loss of voluntary motor control below the injury, including hand function that is critical for independent daily life for quadriplegia. Recently we have made great progress in achieving substantial CST regeneration after SCI using spinal cord neural stem cell or progenitor cell grafts. However, an expected and important finding recently emerged from our RR&D-funded studies: only hindlimb CST axons regenerate into grafts placed into sites of cervical SCI; forelimb CST axons rarely regenerate. These findings raise the hypothesis that enhancing regeneration of forelimb CST axons will significantly improve functional outcomes after SCI when combined with neural stem cell grafts. In the renewal of this grant, we propose to elucidate mechanisms underlying the poor regenerative capacity of the forelimb CST and to test experimental approaches for enhancing forelimb CST regeneration that we hypothesize will further improve forelimb functional recovery after SCI. Specific Aim 1: Use RNA Sequencing to identify molecular mechanisms associated with differences in forelimb-CST and hindlimb-CST axonal regeneration in rats. Understanding mechanisms why forelimb CST does not regenerate is important to help us designing experiments to enhance forelimb CST regeneration. Specific Aim 2: Determine whether transient blockade of forelimb CST synaptic activity enables forelimb CST regeneration. Our recently study showed that forelimb CST axon is highly collateralized in the brain, but hindlimb CST does not. We hypothesize that these extensive collaterals and their synaptic connections of forelimb CST limit their regeneration. Recent studies support this hypothesis since deletion or suppression of Cacna2d2 gene that involve in synaptic activity promotes axon regeneration. Specific Aim 3: Explore whether PTEN/SOCS3 deletion or suppression will increase forelimb CST regeneration and skilled forelimb function recovery. In the previous period of this RR&D grant we found that PTEN/SOCS3 conditional deletion significantly increased overall CST regeneration into a stem cell graft after SCI, but we did not separately label forelimb and hindlimb CST axons. We will determine whether PTEN/SOCS3 genetic deletion or suppression by antisense oligonucleotide therapy specifically enhances forelimb CST regeneration as an alternative mechanism. All studies proposed are supported by preliminary feasibility data and can be conducted by the PI and his collaborators who have extensive experience in SCI research field. Positive findings of this work will substantially enhance our knowledge of central nervous system regeneration mechanisms, and identify paths forward to developing treatments for human SCI.