Maladaptive Remodeling of the Neuromuscular Synapse Following Central Nervous System Injury

项目概要/摘要 中枢神经系统（CNS）损伤，例如中风和脊髓损伤（SCI）是脑损伤的主要原因。 全球残疾负担。减轻中枢神经系统损伤是研究和神经康复的核心 加强复苏的战略。然而，越来越多的证据表明，周围神经系统（PNS）的变化后， 中枢神经系统损伤为治疗研究提供了一个尚未开发的领域。PNS将CNS运动输出与 骨骼肌功能，其中运动单位募集和放电率调节控制。一种马达单元， 一个运动神经元和它所支配的所有肌纤维。为了精确的运动控制，健康的肌纤维接受一个 运动神经元轴突通过单个神经肌肉接头（NMJ）。研究表明， 中风和脊髓损伤后的肌肉麻痹，虽然确切的机制还不清楚。此外，申请人最近 确定了中风后显著的NMJ重塑，包括异常的多轴索神经支配（派）， 接受不止一个轴突输入SCI的试点数据表明，运动单位损失类似于中风，但影响 在NMJ的SCI仍然未被探索。总之，该项目将询问适应不良的PNS重塑 在中枢神经系统损伤残疾的情况下。这项工作将测试靶向轻瘫NMJ的治疗潜力， 脑源性神经营养因子（BDNF），一种已知的运动神经元活力和NMJ可塑性的介质。在 在中风和SCI的鼠模型中，申请人将纵向研究运动行为、运动单位电- 生理学和肌肉收缩性;评估运动神经元池和NMJ的组织病理学;采用分子生物学方法， 生物学技术来定义派的机制;并验证一种新的基因治疗方法。目标1将测试 SCI诱导运动单位功能障碍和NMJ重构的假说，类似于中风。目标2将定义 中风引起的运动单位丧失的病理生理机制;一些预测运动神经元变性是 负责，然而，我们假设发育介质的重新表达诱导运动单位重叠， 派在电生理上表现为假性运动单位丧失。目标3将检验后- 脑源性神经营养因子信号传导的中风减少驱动派，而脑源性神经营养因子通过腺相关病毒递送的正常化 恢复NMJ形式和运动功能。指导培训在翻译神经肌肉生理学从 申办者（在神经肌肉健康方面具有丰富临床前/临床经验的神经肌肉专家， 疾病）由CNS/PNS疾病的基因治疗专家作为共同申办者进行补充，并由 两个关键的合作者（一个是SCI的医生-科学家，一个是具有BDNF信号专长的神经科学家）。这 导师团队与俄亥俄州州立大学的优秀资源和环境紧密相连， 在新的调查领域的增长，并准备申请人的独立性。使用临床相关 方法询问中枢神经系统损伤后运动功能障碍的外周机制，该项目将扩大 对中风和SCI残疾的基本理解，为未来针对外周血管疾病的治疗提供了信息。 改变，并提供关键的培训机会，在学术神经学研究的职业发展。

PROJECT SUMMARY / ABSTRACT Central nervous system (CNS) injuries such as stroke and spinal cord injury (SCI) are major contributors to the global burden of disability. Attenuating CNS damage represents the core of research and neurorehabilitation strategies to enhance recovery. Yet, mounting evidence of peripheral nervous system (PNS) alterations after CNS injury provides an untapped area for therapeutic investigation. The PNS links CNS motor output with skeletal muscle function, where motor unit recruitment and firing rate modulate control. A motor unit is comprised of one motoneuron and all myofibers it innervates. For precision of motor control, healthy myofibers receive one motoneuronal axon via a single neuromuscular junction (NMJ). Studies suggest profound motor unit loss in paretic muscle after stroke and SCI, though exact mechanisms are undefined. Moreover, the applicant recently identified striking NMJ remodeling after stroke, including aberrant polyaxonal innervation (PAI), where NMJs receive more than one axonal input. Pilot data in SCI demonstrate motor unit losses similar to stroke, but impacts of SCI at the NMJ remain unexplored. Taken together, this project will interrogate maladaptive PNS remodeling in the context of CNS injury disability. This work will test the therapeutic potential of targeting paretic NMJs with brain-derived neurotrophic factor (BDNF), a known mediator of motor neuron viability and NMJ plasticity. In murine models of stroke and SCI, the applicant will longitudinally study motor behavior, motor unit electro- physiology, and muscle contractility; assess histopathology of motoneuron pools and NMJs; employ molecular biology techniques to define mechanisms of PAI; and validate a novel gene therapy approach. Aim 1 will test the hypothesis that SCI induces motor unit dysfunction and NMJ remodeling, similar to stroke. Aim 2 will define pathophysiological mechanisms of stroke-induced motor unit loss; some predict motoneuron degeneration is responsible, however we hypothesize re-expression of developmental mediators induces motor unit overlap, with PAI presenting electrophysiologically as spurious motor unit loss. Aim 3 will test the hypothesis that post- stroke reduction in BDNF signaling drives PAI, while normalization of BDNF via adeno-associated viral delivery restores NMJ form and motor function. Mentored training in translational neuromuscular physiology from the Sponsor (a neuromuscular specialist with extensive preclinical/clinical experience in neuromuscular health and disease) is complemented by a gene therapy specialist in CNS/PNS diseases as Co-Sponsor, and supported by two key Collaborators (an SCI physician-scientist, and a neuroscientist with BDNF signaling expertise). This mentorship team dovetails with the excellent resources and environment at The Ohio State University to facilitate growth in new areas of investigation and prepare the applicant for independence. Using clinically-relevant approaches to interrogate peripheral mechanisms of motor dysfunction after CNS injury, this project will expand the fundamental understanding of stroke and SCI disability, inform future therapeutics targeting peripheral alterations, and offer critical training opportunities for career development in academic neurological research.