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

SCI 联盟研究：增强脊髓损伤后皮质脊髓束轴突再生

• 批准号: 9395131
• 负责人: Pengzhe Lu
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395131
• 关键词: Adult; Afghanistan; American; Americas; Anatomy; Animals; Axon; Bilateral; Caring; Cell Transplants; Cervical spinal cord injury; Combined Modality Therapy; Complex; Contusions; Corticospinal Tracts; Data; Disease; Distal; Environment; Feeling; Forelimb; Grant; Growth; Human; Individual; Injury; Intervention; Knowledge; Lesion; Methods; Mission; Modeling; Motor; Movement; Natural regeneration; Neurons; PTEN gene; Paralysed; Patient Care; Peptides; Pharmacology; Process; Rattus; Recovery of Function; Refractory; Rehabilitation therapy; Reporting; Research; Shapes; Site; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Synapses; System; Testing; Time; Training; Transplantation; Veterans; War; Work; axon growth; axon regeneration; base; clinically relevant; combinatorial; design; experience; experimental study; improved; injured; loss of function; motor control; nerve stem cell; neural graft; permissiveness; tool

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.

项目概要 皮质脊髓束（CST）是重要的脊髓上下行运动系统， 控制人类的随意运动。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。为了 例如，有条件地删除磷酸酶和张力蛋白同源物 (PTEN) 或 PTEN 的药理学抑制可增强神经元内在生长能力 增强 SCI 后 CST 的萌芽和再生。神经干移植 细胞（NSC）或神经祖细胞（NPC）作为允许的外部环境 支持 SCI/移植位点的广泛 CST 再生。这些令人兴奋的结果 提供前所未有的机会，这也是本次赠款的主题：合并 NSC 具有 PTEN 药物抑制作用的移植物可产生最广泛的 CST 迄今为止描述的再生。在这项与 VA 相关的工作的逻辑延伸中 康复任务，我们将结合康复训练，假设这将 重塑和加强再生 CST 轴突的连接性，以进一步增强 功能恢复。 拟议研究有 3 个目标。具体目标 1 是确定是否 NPC 移植物和药理 PTEN 抑制相结合可促进 CST 再生和熟练的前肢功能恢复。具体目标 2 是确定 鼻咽癌移植与熟练前肢联合能否达到康复训练 增强CST再生和前肢功能恢复。最后，具体的目标3是 确定是否联合 NPC 移植、药理 PTEN 抑制、 和熟练的前肢伸展康复训练优化 CST 再生和前肢 功能恢复。所有这些目标均基于之前的报告并得到我们的支持 初步可行性数据。这项工作的发现将大大扩展我们的知识 NPC/NSC 治疗 SCI 的一系列系统实验旨在 具有翻译相关性，特别侧重于对退伍军人的干预。