KCC2 and Spinal Cord Injury

KCC2 和脊髓损伤

• 批准号: 10599160
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599160
• 关键词: 4-Aminopyridine; Agonist; Anatomy; Axon; Bilateral; Brain; Cell membrane; Chronic; Contusions; Down-Regulation; Esthesia; Growth; 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; Vertebral column; 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; transmission process

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，宽阔的轴突跨越 脊柱段受损。但是，这些患者中约有一半的肌肉控制总损失 感觉低于伤害水平。一个重要但研究不足的问题是为什么这种不幸的联系 在这些情况下，无法介导功能恢复。人类研究的最新进展表明硬膜外麻醉 刺激与康复训练相结合，使一些长期瘫痪的SCI患者 恢复自愿运动，突出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始时才发生。因此，理解为什么要幸免 SCI后脊柱电路功能失调，以及如何最好地重新激活它，应提供关键的见解 制定新型的SCI功能恢复策略。在交错双侧半剖面的小鼠中， 腰脊髓被剥夺了所有直接脑源性的神经支配，但处于休眠状态 保持在受损的细分市场之间，我们发现使用KCC2激动剂的系统治疗或 KCC2的过表达能够恢复这些瘫痪的小鼠的垫脚能力。我们证明了这样的 操纵能够纠正脊柱继电区内的过度抑制，从而使该绕道电路得以实现 将脑衍生的命令传输到腰椎脊髓的后肢运动指挥中心， 导致功能恢复。通过这些令人兴奋的初步结果，这项拟议的研究将解决 几个相关问题：受伤引起的KCC2下调的机制是什么 受伤的脊髓？为什么实现的功能恢复是部分的，以及如何进一步增强这样 功能恢复？这些电路修改治疗在更临床相关的情况下有什么影响 伤害模型，即严重的挫伤模型？