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）是影响美国军方受伤成员的最残疾条件之一。 不幸的是，SCI患者没有有效的治疗方法。制定新颖的维修策略 减轻SCI的毁灭性本质并在临床上翻译它们是紧迫的医疗需求，可以改善 我们的退伍军人的生活质量。腰运动神经元（MN）是电动机的最终公共途径 输出给后肢。这些MN的任何损害都会导致后肢瘫痪和肌肉萎缩。这 腰肌MN受到直接伤害腰绳或间接损伤的损害 在腰部或胸腔水平（称为高于水平的伤害）上的腰部绳上上方。对于后者，腰部MNS 不受创伤直接伤害，但它们会经历深刻的树突状萎缩和突触 未经脊柱上脊髓和前脊髓轴突。这种改变的Mn形态和突触变化可能 导致后肢肌肉的电动机输出受损，因此运动功能受损。虽然大多数 SCI研究的重点是受伤部位的脊髓再生或保护，很少 研究探索了腰椎MN电路的调节如何影响病理和功能 高级科幻后的后果。我们研究的目的是了解如何改变腰椎MN 在高层SCI之后的解剖学和功能上，有益的恢复治疗如何影响其 重组和功能后果。神经营养蛋白是调节神经元的蛋白质家族 生存，神经突生长，突触可塑性和神经传递。其中，Neurotrophin-3（NT-3）播放 通过促进多个脊柱途径中的轴突生长和突触可塑性，在运动恢复中的特殊作用。 已经提出了外源性施用NT-3作为SCI的一种潜在治疗治疗。这允许 我们提出了第一个假设，即从MNS逆行运输的NT-3释放将导致 MN池周围局部NT-3级别的升高，促进腰运动电路的重塑，并 高于级别的SCI后，增强生理和行为恢复。我们和其他人也表明 仅运动训练改善了SCIS之后的协调运动功能。运动训练也是如此 促进了促进神经元存活和可塑性的脊髓内神经营养因子水平的增加， 进行神经元电路的重组，并改善突触功能和行为。因此，我们 提出第二个假设，即运动训练将协同增强NT-3的影响 重塑免疫的下降脊柱回路并促进其功能连接的形成 与腰部MN。使用成年小鼠T9中度污染SCI模型和腺相关病毒 血清型2向量编码NT-3（AAV2-NT-3）基因转移方法，我们提出了3个特定目的 可见NT-3在SCI后提高恢复和NT-3的长期疗效的机制 那 （1） d 使用临床可行的递送路线进行治疗，（2）确定运动训练是否会增强 NT-3对腰椎MN电路的重塑和高度SCI后功能恢复的影响，以及 （3）确定特定降降途径到腰MN的功能作用 最佳治疗后的腰神经回路和功能恢复。该提案的完成将不会 仅允许我们揭示NT-3/运动训练介导的MN电路重塑的基本机制 而且还要确定针对后肢运动恢复的新治疗策略。