Transplantation of Neural Progenitors as Functional Relay for Spinal Cord Injury

描述(由申请人提供)： 脊髓损伤(SCI)不仅损害脑白质轴索，还损害中央灰质，导致中间神经元和运动神经元节段性丢失。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；脊髓再横断取消了所有恢复。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的再生和移植胚胎神经元的再神经支配，以进一步加强脊髓损伤后功能继发的形成。此外，我们将使用BAC-TRAP翻译图谱来研究功能继发形成的潜在机制，并识别与皮质脊髓束轴突再生有关的基因。最后，我们将把大鼠胚胎脊髓神经前体细胞的研究进展转移到人类胚胎干细胞(ES)方法上。这项工作将揭示脊髓损伤后对神经系统的外部刺激是否可以促进脊髓上轴突的再生，并形成促进功能恢复的移植物介导的神经元中继。此外，这个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和高度相关。

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.