SCI Consortium Study: Enhancing Corticospinal Tract Axonal Regeneration After Spinal Cord Injury

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Project Summary Corticospinal tract (CST) is an important supraspinal descending motor system that controls voluntary movement in humans. Good progress has been made in recent years to elicit CST axonal regeneration and re-connectivity after spinal cord injury (SCI). For example, conditional deletion of phosphatase and tensin homolog (PTEN) or pharmacological suppression of PTEN that boosts neuronal intrinsic ability to grow enhances CST sprouting and regeneration after SCI. Transplantation of neural stem cells (NSCs) or neural progenitor cells (NPCs) as a permissive extrinsic environment supports extensive CST regeneration into SCI/transplant site. These exciting results provide an unprecedented opportunity that is the subject of this grant: combine NSC grafts with pharmacological suppression of PTEN to generate the most extensive CST regeneration described to date. In a logical extension of this work related to the VA's rehabilitation mission, we will combine rehabilitation training, hypothesizing that this will re-shape and strengthen connectivity of regenerating CST axons to further enhance functional recovery. There are 3 Aims in the proposed studies. The specific Aim 1 is to determine whether combined NPC grafts and pharmacological PTEN suppression promote CST regeneration and skilled forelimb functional recovery. The specific Aim 2 is to determine whether combined NPC transplants and skilled forelimb reach rehabilitation training enhance CST regeneration and forelimb functional recovery. Last, the specific Aim 3 is to determine whether combined NPC transplants, pharmacological PTEN suppression, and skilled forelimb reach rehabilitation training optimize CST regeneration and forelimb functional recovery. All these Aims are based on previous reports and supported by our preliminary feasibility data. Findings of this work will substantially extend our knowledge of NPC/NSC treatments for SCI, in a systematic set of experiments designed to be translationally relevant and specifically focused on interventions for Veterans.