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.

项目摘要 皮质脊髓道（CST）是一个重要的上脊髓降落的运动系统 控制人类的自愿运动。近年来取得了良好的进步 引起脊髓损伤（SCI）后的CST轴突再生和重新连接。为了 例如，磷酸酶和Tensin同源物（PTEN）或 PTEN的药理学抑制，增长了神经元内固有能力 在SCI后增强CST发芽和再生。神经茎的移植 细胞（NSC）或神经祖细胞（NPC）作为允许的外部环境 支持广泛的CST再生到科幻/移植部位。这些令人兴奋的结果 提供本赠款主题的前所未有的机会：结合NSC 具有药理学抑制PTEN的移植物可产生最广泛的CST 迄今为止描述的再生。在与VA有关的这项工作的逻辑扩展中 康复任务，我们将结合康复培训，假设这将是 重新形状并增强再生CST轴突的连通性，以进一步增强 功能恢复。 拟议的研究有3个目标。具体目的1是确定是否 NPC移植物和药理学PTEN抑制促进CST 再生和熟练的前肢功能恢复。具体目的2是确定 NPC移植和熟练的前肢是否合并 增强CST再生和前肢功能恢复。最后，具体目标3是 确定NPC移植的合并，药理PTEN抑制， 和熟练的前肢到达康复训练优化CST再生和前肢 功能恢复。所有这些目标都是基于以前的报告，并得到了我们的支持 初步可行性数据。这项工作的发现将大大扩展我们的知识 SCI的NPC/NSC处理，在一组系统的实验中 翻译相关，专门针对退伍军人的干预措施。