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

脊髓损伤后恢复运动功能的新型组合方法

• 批准号: 9894862
• 负责人: Yutaka Yoshida
• 金额: $ 39.87万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894862
• 关键词: Affect; Anatomy; Axon; Back Injuries; Biological Assay; Cervical; Cervical spinal cord injury; Data; Dorsal; Electrophysiology (science); Failure; Future; Gene Transfer; Genetic Models; Growth; Human; In Vitro; Injury; Interneurons; Intervention; Knowledge; Label; Lentivirus Vector; Lesion; Location; Modeling; Motor; Mus; Muscle; Mutant Strains Mice; Natural regeneration; Neurons; PTEN gene; Paralysed; Recovery; Reporting; Research; Signal Transduction; Site; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Synapses; Testing; Walking; axon growth; axon injury; base; combinatorial; design; improved; injured; mad itch virus; motor recovery; mutant; novel; optogenetics; patch clamp; receptor

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.

摘要（总结）：脊髓损伤（SCI）常因以下原因导致永久性瘫痪： 受伤的轴突无法再生。尽管受伤的 CS 轴突不会重新生长超过 SCI后的病变，它们与上面的本体脊髓神经元形成新的连接 导致这些损伤中恢复有限的病变（吻侧） 模型。在这项研究中，我们提出了双管齐下的策略，以同时诱导重新 受损的皮质脊髓 (CS) 轴突超出病变部位并增强 损伤后CS轴突和本体脊髓神经元之间连接的重塑 SCI。通过减少磷酸酶和张力蛋白同源物可以促进 CS 轴突生长 (Pten) 感觉运动皮层的活动。我们的初步数据显示 CS 增加 缺乏编码 semaphorin6D 受体的 PlexA1 的小鼠 SC 后的连接。自从 PlexA1 突变体中受伤的 CS 轴突不会超出病变部位，我们初步认为 数据强烈表明受伤的 CS 轴突和本体脊髓之间的新联系 脊髓损伤后，神经元通过未受伤的腹侧区域得到增强，以补偿 CS输入的损失。基于这些初步数据，本研究的中心假设 建议将 Sema6D-PlexA1 和 Pten 信号的组合调制 促进CS与本体脊髓神经元连接的重新布线以及神经元的重新生长 脊髓损伤后颈部 CS 轴突受伤。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，我们将确定是否 删除感觉运动皮层中的 PlexA1 和 Pten 将增强连接性 受损的 CS 轴突和本体脊髓神经元之间的影响程度大于损失程度 单独的 PlexA1 或 Pten。在目标 2 中，我们将确定 PlexA1、Pten 或 PlexA1/Pten 缺失增加了受伤的 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 PlexA1 和 Pten。