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.
Spinal Cord Injury (SCI) is damage to the spinal cord that results in permanent loss of function such as mobility or feeling below injury. There are approximately 282,000 Americans living with spinal cord injuries, and approximately 20,000 of those injured are Veterans (data from Paralyzed Veterans of America). The number of such injuries is increasing as a result of the Afghanistan war. Thus, care and treatment of spinal cord injured veterans is important to the VA patient care mission. Corticospinal tract (CST) is a very important descending motor system that controls voluntary movement in humans, and appears to be the most refractory motor system from which to elicit regeneration. The proposed study is to combine neural progenitor cell transplants, pharmacological PTEN suppression and rehabilitation training to enhance CST axonal regeneration and functional recovery after SCI. The successful of this project will benefit those veterans and civilians who suffer SCI.
