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: 8977429
• 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/8977429
• 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; 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.

描述(由申请人提供)： 试点项目摘要脊髓损伤(SCI)通常不仅损害往返大脑的白质轴索，还损害中央灰质，导致中间神经元和运动神经元的节段性损失。神经干细胞或神经前体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，而且还可以在因损伤而断开的脊髓节段之间起到功能上的中继作用。我们的初步数据为这一功能继发假说提供了强有力的支持，显示宿主轴突长入移植到脊髓损伤部位的胚胎神经元中，并显著地出现移植到宿主脊髓中的轴突。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继电器，导致行为恢复；移植物上方的脊髓重新横断取消了所有恢复。这些发现表明，胚胎神经元可以作为功能继电器，恢复脊髓损伤后的功能性突触连接。本实验的目的是通过确定人胎脊髓神经元，特别是高比例的兴奋性中间神经元，在大鼠脊髓全横断后是否能形成类似于恢复运动活动的功能继电器，从而将这些发现应用于临床。我们与神经干细胞公司合作，提供目前FDA批准用于治疗肌萎缩侧索硬化症(ALS)的临床试验的人类胚胎脊髓神经元的临床等级。这一试点项目的成功可能会导致一项全面的功绩审查翻译研究。这项研究的目标与退伍军人管理局的患者护理任务直接和高度相关。