KCC2 and Spinal Cord Injury

KCC2 和脊髓损伤

• 批准号: 10094088
• 负责人: ZHIGANG HE
• 金额: $ 42.02万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094088
• 关键词: 4-Aminopyridine; Address; Agonist; Anatomy; Axon; Bilateral; Brain; Cell membrane; Chronic; Contusions; Down-Regulation; Esthesia; Hindlimb; Human; IGF1 gene; Immunohistochemistry; In Situ Hybridization; Injury; Lesion; Light; Lumbar spinal cord structure; Mediating; Membrane; Messenger RNA; Modeling; Motor; Motor Cortex; Motor Neurons; Movement; Mus; Muscle; Muscular Atrophy; Neurons; Paralysed; Pathway interactions; Patients; Play; Proteins; Rattus; Recovery of Function; Rehabilitation therapy; Role; Spinal; Spinal Cord; Spinal cord damage; Spinal cord injury; Testing; Time; Training; base; clinically relevant; deprivation; design; excitatory neuron; functional restoration; glial cell-line derived neurotrophic factor; inhibitory neuron; insight; nerve supply; novel; novel strategies; osteopontin; overexpression; restoration

Abstract/Project Summary Most human spinal cord injuries (SCIs) are anatomically incomplete, with spared axons spanning the damaged spinal segments. However, about a half of these patients have a total loss of muscle control and sensation below the injury level. An important but under-studied question is why such spared connections fail to mediate functional recovery in these cases. Recent advances in human studies show that epidural stimulation combined with rehabilitative training allows some chronically paralyzed patients with SCI to regain voluntary movement, highlights the feasibility of reactivating such dormant spinal circuitry. However, the limited functional recovery only occurs when the stimulation is on. Thus, understanding why this spared spinal circuitry is dysfunctional after SCI, and how it can best be reactivated, should provide key insights into developing novel functional restoration strategies for SCI. In mice with staggered bilateral hemisections, in which the lumbar spinal cord is deprived of all direct brain-derived innervation but dormant relay circuits remain between the damaged segments, we discovered that systematic treatment with a KCC2 agonist, or over-expression of KCC2, is able to restore stepping ability in these paralyzed mice. We showed that such manipulations are able to correct over-inhibition within the spinal relay zone, allowing this detour circuit to transmit the brain-derived commands to the hindlimb motor command center in the lumbar spinal cord, leading to functional recovery. With these exciting preliminary results, this proposed study will address several related questions: what is the mechanism underlying injury-induced KCC2 down-regulation in injured spinal cord? Why the achieved functional recovery is partial and how to further enhance such functional recovery? What are the effects of these circuit-modifying treatments in more clinically relevant injury models, namely severe contusion models?

摘要/项目摘要 大多数人类脊髓损伤（SCI）在解剖学上是不完整的，幸存的轴突横跨整个脊髓 受损的脊柱节段。然而，大约一半的患者完全丧失肌肉控制能力，并且 低于损伤水平的感觉。一个重要但尚未充分研究的问题是为什么这种不受影响的连接 在这些情况下无法介导功能恢复。人体研究的最新进展表明，硬膜外麻醉 刺激与康复训练相结合，使一些患有 SCI 的慢性瘫痪患者能够 恢复随意运动，凸显了重新激活这种休眠脊髓回路的可行性。然而， 有限的功能恢复仅在刺激开启时发生。因此，了解为什么这可以幸免 脊髓损伤后脊髓回路功能失调，以及如何最好地重新激活它，应该提供重要的见解 开发新的 SCI 功能恢复策略。在双侧交错半切的小鼠中， 其中腰脊髓被剥夺了所有直接的脑源性神经支配，但休眠的中继电路 保留在受损节段之间，我们发现用 KCC2 激动剂进行系统治疗，或 KCC2 的过度表达能够恢复这些瘫痪小鼠的行走能力。我们证明了这样的 操作能够纠正脊髓中继区内的过度抑制，从而使该迂回回路能够 将来自大脑的命令传输到腰脊髓的后肢运动指挥中心， 从而导致功能恢复。有了这些令人兴奋的初步结果，这项拟议的研究将解决 几个相关的问题：损伤诱导的 KCC2 下调的机制是什么？ 脊髓受伤？为什么实现的功能恢复是部分的以及如何进一步增强这种功能 功能恢复？这些电路改造治疗在临床上有何影响？ 损伤模型，即严重挫伤模型？