Restore Synaptic Connectivity of Injured Spinal Cord with Human Embryonic Neurons

恢复受损脊髓与人类胚胎神经元的突触连接

• 批准号: 8399329
• 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: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399329
• 关键词: Acute; Adult; Afghanistan; American; Americas; Amyotrophic Lateral Sclerosis; Axon; Behavioral; Brain; Brain Stem; Caring; Cell Survival; Cell Transplants; Central Nervous System Diseases; Cervical; Chest; Chronic; Clinical; Clinical Treatment; Clinical Trials; Corticospinal Tracts; Data; Electrons; Embryo; Environment; Excitatory Synapse; FDA approved; Feeling; Future; Genes; Glutamates; Goals; Green Fluorescent Proteins; Growth; Human; Inhibitory Synapse; Injury; Interneurons; Iraq; Knowledge; Lead; Lesion; Life; Locomotion; Microscopic; Mission; Modeling; Motor; Motor Activity; Motor Neurons; Natural regeneration; Neuroglia; Neurons; Paralysed; Patient Care; Phenotype; Pilot Projects; Process; Rattus; Recovery; Research; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Stem cells; Synapses; T-Cell Leukemia; Techniques; Thoracic spinal cord structure; Transgenic Organisms; Translations; Transplantation; Veterans; War; axon regeneration; base; central gray matter; embryonic stem cell; fetal; gray matter; human embryonic stem cell; injured; loss of function; nerve stem cell; nervous system disorder; progenitor; public health relevance; repaired; research study; synaptogenesis; translational study; white matter

DESCRIPTION (provided by applicant): Pilot Project Summary 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 ingrowth of host axons into embryonic neurons grafted to sites of spinal cord injury, and remarkable emergence of grafted axons into the host spinal cord. More importantly, grafted embryonic neurons supported formation of functional electrophysiological relays across sites of complete spinal transection, resulting in behavioral recovery; spinal re-transection above the graft abolished all recovery. These findings indicate that embryonic neurons can serve as functional relays to restore functional synaptic connectivity after SCI. The purpose of this pilot project is to bring these findings to clinical practicality by determining whether human fetal spinal cord neurons, especially high proportion of excitatory interneurons, can form similar functional relays to restor locomotion activity after complete spinal cord transection in rat model. We collaborate with Neuralstem Inc. that provides the clinical grade of human fetal spinal cord neurons that are currently approved by FDA for clinical trial for treatment of amyotrophic lateral sclerosis (ALS). The successful of this Pilot Project could lead to a full Merit Review translational study. 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）： 试点项目摘要 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种功能中继假说提供了强有力的支持，显示宿主轴突向内生长到移植到脊髓损伤部位的胚胎神经元中，并且移植轴突显着出现到宿主脊髓中。更重要的是，移植的胚胎神经元支持在完全脊髓横断部位形成功能性电生理中继，从而导致行为恢复；脊柱再次横断，上面的移植物全部废止恢复。这些发现表明，胚胎神经元可以作为功能中继，在 SCI 后恢复功能性突触连接。该试点项目的目的是通过确定人类胎儿脊髓神经元，特别是高比例的兴奋性中间神经元，是否可以在大鼠模型中完全脊髓横断后形成类似的功能中继以恢复运动活动，从而将这些发现应用于临床实用。我们与 Neuralstem Inc. 合作，该公司提供临床级的人类胎儿脊髓神经元，目前已获得 FDA 批准用于治疗肌萎缩侧索硬化症 (ALS) 的临床试验。该试点项目的成功可能会导致全面的绩效审查转化研究。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。