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

项目摘要 皮质脊髓束（CST）是重要的脊髓上下行运动系统， 控制着人类的自主运动近年来取得了良好的进展 诱导脊髓损伤（SCI）后CST轴突再生和重新连接。为 例如，磷酸酶和张力蛋白同源物（PTEN）的条件性缺失或 增强神经元内在生长能力的PTEN的药理学抑制 增强SCI后CST的发芽和再生。移植神经干 细胞（NSC）或神经祖细胞（NPCs）作为允许的外部环境 支持SCI/移植部位的广泛CST再生。这些令人兴奋的结果 提供了一个前所未有的机会，这是本赠款的主题：联合收割机NSC 具有药理学抑制的PTEN的移植物产生最广泛的CST 再生描述至今。在与退伍军人事务部有关的这项工作的逻辑延伸中， 康复使命，我们将联合收割机康复训练，假设这将 重塑和加强再生CST轴突的连接，以进一步增强 功能恢复 在拟议的研究中有3个目的。具体目标1是确定是否 联合NPC移植和药物抑制PTEN促进CST 再生和熟练的前肢功能恢复。具体目标2是确定 NPC联合移植及熟练前肢是否达到康复训练 促进CST再生和前肢功能恢复。最后，具体目标3是 以确定是否联合NPC移植，药理学PTEN抑制， 熟练的前肢伸展康复训练优化CST再生和前肢 功能恢复所有这些目标都基于之前的报告并得到我们的支持 初步可行性数据。这项工作的结果将大大扩展我们的知识 NPC/NSC治疗SCI，在一组系统的实验设计， 与退伍军人相关，并特别关注退伍军人的干预措施。

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.