A novel combinatorial approach to restore motor function after spinal cord injury

摘要（摘要）：脊髓损伤（SCI）往往会导致永久性瘫痪，由于 受损轴突无法再生。虽然受伤的CS轴突不会重新生长， 脊髓损伤后，它们与脊髓本体神经元形成新的连接， （嘴侧）病变导致这些损伤中观察到的恢复有限 模型在这项研究中，我们提出了双管齐下的策略来同时诱导重新激活。 损伤的皮质脊髓（CS）轴突的生长超出病变部位，并增强 损伤的CS轴突和脊髓本体神经元之间的连接重建 SCI.降低磷酸酶和张力蛋白同源物可促进CS轴突生长 （Pten）在感觉运动皮层的活动。我们的初步数据显示， 在缺乏编码脑信号蛋白6D受体的PlexA 1的小鼠中SC后的连接。以来 PlexA 1突变体中受损的CS轴突不能通过病变部位，我们的初步研究表明， 数据有力地表明，损伤的CS轴突和本体脊髓之间的新连接， 神经元通过SCI后未受伤的腹侧区域增强，以补偿 CS输入的损失。根据这些初步数据，这一假设的核心是： 建议是Sema 6D-PlexA 1和Pten信令的组合调制将 促进CS连接与本体脊髓神经元的重新连接以及 脊髓损伤后颈脊髓轴突损伤。因此，这些干预措施将改善 功能性CS连接和运动恢复。在目标1中，我们将确定 感觉运动皮层中PlexA 1和Pten的缺失将增强连接 损伤的CS轴突和本体脊髓神经元之间的联系比 PlexA 1或Pten单独。在目标2中，我们将确定PlexA 1、Pten或 PlexA 1/Pten缺失增加了受损CS神经元和肌肉之间的回路。 最后，在目标3中，我们将检查缺乏运动能力的小鼠的运动恢复是否得到增强。 感觉运动皮层中的PlexA 1和Pten。

Abstract (Summary): Spinal cord injury (SCI) often causes permanent paralysis due to failure of injured axons to regenerate. Although injured CS axons do not re-grow beyond the lesion after SCI, they form new connections with propriospinal neurons above (rostral to) the lesion which contributes to the limited recovery seen in these injury models. In this study, we propose two-pronged strategies to simultaneously induce re- growth of injured corticospinal (CS) axons beyond the lesion site and enhance remodeling of connectivity between injured CS axons and propriospinal neurons after SCI. CS axonal growth can be promoted by reducing phosphatase and tensin homolog (Pten) activity in the sensorimotor cortex. Our preliminary data reveal increased CS connectivity after SC in mice lacking PlexA1 encoding a semaphorin6D receptor. Since injured CS axons in PlexA1 mutants do not pass beyond the lesion site, our preliminary data strongly suggest that new connections between injured CS axons and propriospinal neurons are enhanced through the uninjured ventral regions after SCI to compensate for the loss of CS inputs. Based on these preliminary data, the central hypothesis of this proposal is that a combined modulation of Sema6D-PlexA1 and Pten signaling will facilitate rewiring of CS connectivity with propriospinal neurons as well as re-growth of injured CS axons after SCI at cervical levels. Therefore, these interventions will improve functional CS connectivity and motor recovery. In Aim 1, we will determine whether deletion of both PlexA1 and Pten in the sensorimotor cortex will enhance connectivity between injured CS axons and propriospinal neurons to a greater degree than the loss of PlexA1 or Pten alone. In Aim 2, we will determine whether PlexA1, Pten, or PlexA1/Pten deletion increases circuits between injured CS neurons and muscles. Finally, in Aim 3, we will examine whether motor recovery is enhanced in mice lacking PlexA1 and Pten in the sensorimotor cortex.