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）： 脊髓损伤（SCI）通常不仅损害传递大脑信号的白色轴突束，而且损害中央灰质，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替代丢失的神经元和神经胶质，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。我们的初步数据提供了强有力的支持，这一功能中继假说，显示宿主轴突长入胚胎神经元移植到网站的脊髓损伤，并显着出现移植轴突到宿主脊髓。更重要的是，移植的胚胎神经元支持形成功能性电生理继电器在整个网站的完整脊髓横断，导致行为恢复;脊髓再横断以上的移植废除所有恢复。这些发现表明，胚胎神经元可以作为功能中继，以恢复功能性突触连接后SCI。本试验项目的目的是通过确定人胎儿脊髓神经元，特别是高比例的兴奋性中间神经元，是否可以形成类似的功能继电器，以恢复大鼠模型脊髓完全横断后的运动活动，从而将这些发现应用于临床实践。我们与Neuralstem Inc.合作其提供了目前被FDA批准用于治疗肌萎缩性侧索硬化症（ALS）的临床试验的人胎儿脊髓神经元的临床等级。该试点项目的成功可能会导致全面的优点审查转化研究。本研究的目标与VA患者护理使命直接且高度相关。