Transplantation of Neural Progenitors as Functional Relay for Spinal Cord Injury

描述（由申请人提供）： 脊髓损伤（SCI）不仅损伤了传递大脑信号的白色轴突，而且损伤了中央灰质，导致中间神经元和运动神经元的节段性丢失。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。我们的初步数据为这种功能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脊髓完全横断部位形成功能性电生理中继，导致行为恢复;脊髓再横断消除了所有恢复。这些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神经支配，以进一步加强SCI后功能中继的形成。此外，我们将研究潜在的功能中继形成的机制，并确定负责皮质脊髓束轴突再生的基因，使用BAC-TRAP翻译谱。最后，我们将从大鼠胚胎脊髓神经元祖细胞的工作进展转移到人类胚胎干细胞（ES）的方法。这项工作将揭示SCI后神经系统的外源性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，促进功能恢复。此外，这个模型系统将提供一个丰富的机会，确定轴突再生的分子机制。本研究的目标与VA患者护理使命直接且高度相关。

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.