Exercise and NT-3-mediated lumbar motoneuron plasticity and recovery after SCI

SCI 后运动和 NT-3 介导的腰椎运动神经元可塑性和恢复

• 批准号: 10329902
• 负责人: Chandler Walker
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329902
• 关键词: Adult; Affect; Anatomy; Atrophic; Axon; Behavior; Behavioral; Cervical; Chest; Chronic; Clinical; Dependovirus; Development; Effectiveness; Electrophysiology (science); Exercise; Gene Expression Profile; Gene Transfer; Goals; Hindlimb; Human; Impairment; Injury; Locomotor Recovery; Mediating; Medical; Military Personnel; Modeling; Morphology; Motor; Motor Neurons; Motor Pathways; Motor output; Mus; Muscle; Muscular Atrophy; Natural regeneration; Nature; Neurites; Neuronal Plasticity; Neurotrophin 3; Paralysed; Pathologic; Pathway interactions; Phase; Physiological; Play; Protein Family; Quality of life; Recovery; Recovery of Function; Research; Role; Route; Serotyping; Site; Spinal; Spinal Cord Contusions; Spinal cord injury; Spinal cord injury patients; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Therapeutic; Thoracic spinal cord structure; Training; Training Programs; Translating; Trauma; United States; Veterans; Viral; axon growth; combinatorial; effective therapy; exercise training; experimental study; gene therapy; improved; injured; member; motor impairment; neural circuit; neuronal circuitry; neuronal survival; neurotransmission; neurotrophic factor; novel; novel therapeutic intervention; novel therapeutics; optimal treatments; repair strategy; restoration; restorative treatment; retrograde transport; sciatic nerve; signature molecule; spinal pathway; synaptic function; treatment comparison; vector

Spinal cord injury (SCI) is among the most disabling conditions affecting wounded members of the U.S. military. Unfortunately, no effective treatment has been available for SCI patients. Developing novel repair strategies to mitigate the devastating nature of SCI and translating them clinically are urgent medical needs that will improve quality of life of our veterans with SCI. The lumbar motoneurons (MNs) are the final common pathway for motor output to the hindlimbs. Any impairment of these MNs can cause hindlimb paralysis and muscle atrophy. The lumbar MNs could be impaired by a direct injury to the lumbar cord or by an indirect injury occurring at levels above the lumbar cord at cervical or thoracic levels (called above-level injuries). For the latter, the lumbar MNs are not directly injured by the trauma, but they undergo profound dendritic atrophy and synaptic stripping from denervated supraspinal and propriospinal axons. Such altered MN morphological and synaptic changes could result in impaired motor outputs to hindlimb muscles and therefore impaired locomotor functions. While most SCI studies have been focused on the regeneration or protection of injured spinal cord at the site of injury, few studies have explored how modulation of lumbar MN circuitry would affect pathological and functional consequences after an above-level SCI. The goal of our research is to understand how lumbar MNs are altered anatomically and functionally after an above-level SCI and how a beneficial restorative treatment affects their reorganization and functional consequences. Neurotrophins are a family of proteins that regulate neuronal survival, neurite outgrowth, synaptic plasticity and neurotransmission. Among them, Neurotrophin-3 (NT-3) plays a particular role in motor restoration by promoting axon growth and synaptic plasticity in multiple spinal pathways. Exogenous administration of NT-3 has been proposed as one potential therapeutic treatment for SCI. This allows us to propose the first hypothesis that the release of retrogradely transported NT-3 from MNs will result in an elevation of local NT-3 levels around the MN pools, promoting remodeling of lumbar motor circuitry, and enhancing physiological and behavioral recoveries following an above-level SCI. We and others also showed exercise training alone improved coordinated motor function following SCIs. Exercise training also contributed to the increased levels of intraspinal neurotrophic factors that promote neuronal survival and plasticity, to the reorganization of neuronal circuitry, and to improvements in synaptic function and behavior. Therefore, we propose the second hypothesis that exercise training will synergistically enhance the effect of NT-3 perhaps by remodeling the spared descending spinal circuits and facilitating the formation of their functional connections with lumbar MNs. Using an adult mouse T9 moderate contusive SCI model and an adeno-associated virus serotype 2 vector encoding NT-3 (AAV2-NT-3) gene transfer approach, we propose 3 Specific Aims to etermine the mechanism by which NT-3 improves recovery after SCI and the long-term efficacy of the NT-3 that (1) d treatment using a clinically feasible delivery route, (2) determine whether exercise training will enhance the effects of NT-3 on the remodeling of lumbar MN circuitry and functional recovery after an above-level SCI, and (3) determine the functional roles of specific descending pathways to lumbar MNs in their ability to modulate lumbar neural circuitry and functional recovery after the optimal treatment. Completion of this proposal will not only allow us to reveal fundamental mechanisms of NT-3/exercise training-mediated remodeling of MN circuitry but also to identify new therapeutic strategies targeting hindlimb locomotor recovery.

脊髓损伤 (SCI) 是影响美国军人受伤的最严重的疾病之一。 不幸的是，目前尚无针对 SCI 患者的有效治疗方法。开发新颖的修复策略 减轻 SCI 的破坏性并将其转化为临床是迫切的医疗需求，这将改善 SCI 退伍军人的生活质量。腰椎运动神经元 (MN) 是运动神经元的最终共同通路 输出至后肢。这些 MN 的任何损伤都会导致后肢瘫痪和肌肉萎缩。这 腰椎 MN 可能因腰脊髓的直接损伤或水平发生的间接损伤而受损 颈椎或胸部腰椎上方的损伤（称为上方损伤）。对于后者，腰椎 MN 并没有直接受到创伤的伤害，但它们经历了严重的树突萎缩和突触剥离 脊髓上和本体轴突去神经。这种改变的 MN 形态和突触变化可能 导致后肢肌肉的运动输出受损，从而损害运动功能。虽然大多数 SCI 研究主要集中在损伤部位的损伤脊髓的再生或保护，很少有 研究探索了腰椎 MN 回路的调节如何影响病理和功能 以上级别 SCI 后的后果。我们研究的目标是了解腰椎 MN 是如何改变的 以上级别 SCI 后的解剖学和功能性以及有益的恢复性治疗如何影响他们 重组和功能后果。神经营养素是调节神经元的蛋白质家族 存活、神经突生长、突触可塑性和神经传递。其中，神经营养蛋白-3（NT-3）发挥着 通过促进多个脊髓通路中的轴突生长和突触可塑性，在运动恢复中发挥特殊作用。 NT-3 的外源性给药已被提议作为 SCI 的一种潜在治疗方法。这允许 我们提出第一个假设，即 MN 中逆行转运的 NT-3 的释放将导致 MN 池周围局部 NT-3 水平升高，促进腰椎运动回路重塑，以及 增强以上级别 SCI 后的生理和行为恢复。我们和其他人还展示了 单独的运动训练可以改善脊髓损伤后的协调运动功能。运动训练也 有助于提高椎管内神经营养因子的水平，从而促进神经元的存活和可塑性， 神经元回路的重组以及突触功能和行为的改善。因此，我们 提出第二个假设，即运动训练可能会协同增强 NT-3 的效果 重塑幸存的脊髓下行回路并促进其功能连接的形成 与腰椎 MN。使用成年小鼠 T9 中度挫伤性 SCI 模型和腺相关病毒 血清型 2 载体编码 NT-3 (AAV2-NT-3) 基因转移方法，我们提出 3 个具体目标 确定 NT-3 改善 SCI 后恢复的机制以及 NT-3 的长期疗效 那 (1) d 使用临床上可行的给药途径进行治疗，（2）确定运动训练是否会增强 NT-3 对腰椎 MN 回路重塑和以上级别 SCI 后功能恢复的影响，以及 (3) 确定腰椎 MN 的特定下行通路在调节能力中的功能作用 最佳治疗后腰部神经回路和功能恢复。本提案的完成不会 只允许我们揭示 NT-3/运动训练介导的 MN 回路重塑的基本机制 还旨在确定针对后肢运动恢复的新治疗策略。