Transplantation of Neural Progenitors as Functional Relay for Spinal Cord Injury

神经祖细胞移植作为脊髓损伤的功能中继

• 批准号: 8330749
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330749
• 关键词: Acute; Adult; Affinity Chromatography; Afghanistan; American; Americas; Animal Experimentation; Axon; Bacterial Artificial Chromosomes; Behavioral; Biological Models; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Caring; Cell Survival; Cell Transplants; Cells; Cervical; Chest; Chronic; Clinical; Corticospinal Tracts; Data; Dependovirus; Electron Microscopy; Electrophysiology (science); Embryo; Environment; Feeling; Future; Genes; Goals; Green Fluorescent Proteins; Human; Injury; Interneurons; Iraq; Knowledge; Lesion; Life; Mediating; Mission; Molecular; Motor; Motor Neurons; Natural regeneration; Neuroglia; Neurons; Outcome; Paralysed; Patient Care; Process; Property; Rattus; Recovery; Recovery of Function; Replacement Therapy; Research; Ribosomes; Serotyping; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Cord Lesions; Spinal Cord transection injury; Spinal cord injury; Stem cells; Synapses; System; Techniques; Thoracic spinal cord structure; Transgenic Mice; Transgenic Organisms; Translating; Translations; Transplantation; Veterans; War; Work; axon growth; axon regeneration; base; behavior test; cell type; central gray matter; functional restoration; gray matter; human embryonic stem cell; immunocytochemistry; injured; loss of function; mouse model; nerve stem cell; nerve supply; neural graft; neural stimulation; neuronal replacement; neurotrophic factor; novel; progenitor; reconstitution; reinnervation; research study; synaptogenesis; white matter

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) often damages not only white matter axon tracts that carry signals to and from the brain, but also the central gray matter, causing segmental losses of interneurons and motor neurons. Transplantation of neural stem cells or neural progenitors not only potentially replaces lost neurons and glia, but could also serve as a functional relay between spinal cord segments that are disconnected by injury. Our preliminary data provide strong support for this functional relay hypothesis, showing grafted embryonic neurons support formation of functional electrophysiological relays across sites of complete spinal transection, resulting in behavioral recovery; spinal re- transection abolished all recovery. The proposed studies will determine whether extrinsic neurotrophins promote host supraspinal axon regeneration and re-innervation of grafted embryonic neurons to further strengthen formation of functional relays after SCI. In addition, we will examine mechanisms underlying functional relay formation and identify genes responsible for corticospinal tract axonal regeneration, using BAC-TRAP translational profiling. Lastly, we will transfer advances from rat embryonic spinal cord neuronal progenitor work to human embryonic stem (ES) cell approaches. This work will reveal whether extrinsic stimulation of neural systems after SCI can enhance supraspinal axonal regeneration and form graft-mediated neuronal relays that facilitate functional recovery. Further, this model system will provide a rich opportunity for identifying molecular mechanisms underlying axonal regeneration. The goals of this research are directly and highly relevant to the VA patient care mission. PUBLIC HEALTH RELEVANCE: 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 250,000 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 Iraq and Afghanistan war. Thus, care and treatment of spinal cord injured veterans is important to the VA patient care mission. The use of neural stem cells or progenitors as a functional relay is a very promised experimental study. Results from the current proposal will provide important knowledge that could form the basis for generating future therapies for acute and chronic SCI.

描述（由申请人提供）： 脊髓损伤 (SCI) 通常不仅会损害将信号传入和传出大脑的白质轴突束，还会损害中央灰质，导致中间神经元和运动神经元的节段性损失。神经干细胞或神经祖细胞的移植不仅有可能取代丢失的神经元和神经胶质细胞，而且还可以作为因损伤而断开的脊髓节段之间的功能中继。我们的初步数据为这一功能性中继假说提供了强有力的支持，表明移植的胚胎神经元支持在完全脊柱横断部位形成功能性电生理中继，从而导致行为恢复；脊柱再横断术使所有恢复无效。拟议的研究将确定外源性神经营养因子是否促进宿主脊髓上轴突再生和移植胚胎神经元的重新神经支配，以进一步加强 SCI 后功能中继的形成。此外，我们将使用 BAC-TRAP 翻译分析来检查功能中继形成的机制，并鉴定负责皮质脊髓束轴突再生的基因。最后，我们将把大鼠胚胎脊髓神经祖细胞工作的进展转移到人类胚胎干（ES）细胞方法上。这项工作将揭示 SCI 后神经系统的外在刺激是否可以增强脊髓上轴突再生并形成移植物介导的神经元中继，从而促进功能恢复。此外，该模型系统将为识别轴突再生的分子机制提供丰富的机会。这项研究的目标与退伍军人管理局的患者护理任务直接且高度相关。 公共卫生相关性： 脊髓损伤 (SCI) 是指脊髓损伤，导致永久性功能丧失，例如活动能力或受伤后的感觉。大约有 250,000 名美国人患有脊髓损伤，其中大约 20,000 名受伤者是退伍军人（数据来自美国瘫痪退伍军人协会）。由于伊拉克和阿富汗战争，此类伤害的人数正在增加。因此，脊髓损伤退伍军人的护理和治疗对于退伍军人管理局的患者护理任务非常重要。使用神经干细胞或祖细胞作为功能中继是一项非常有前途的实验研究。当前提案的结果将提供重要的知识，为未来急性和慢性 SCI 的治疗奠定基础。