Maladaptive Remodeling of the Neuromuscular Synapse Following Central Nervous System Injury

中枢神经系统损伤后神经肌肉突触的适应不良重塑

基本信息

批准号：
10569935
负责人：
Maria Helen Harley Balch
金额：
$ 7.2万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569935
关键词：
Acute Affect Aging Applications Grants Area Axon Behavioral Brain Infarction Brain-Derived Neurotrophic Factor Central Nervous System Chronic Clinical Clinical Research Communication Complement Confocal Microscopy Data Development Disease Electrophysiology (science)Environment Etiology Event Exhibits Faculty Fellowship Fostering Functional disorder Future Growth Health Histologic Histopathology Horns Immunohistochemistry Investigation Ischemia Ischemic Stroke Lesion Link Longitudinal Studies Measures Mediating Mediator Mentors Mentorship Methodology Molecular Molecular Biology Techniques Morphology Motor Motor Neurons Motor output Muscle Muscle Fibers Muscle function Nerve Degeneration Nervous System Trauma Neurologic Neuromuscular Diseases Neuromuscular Junction Neurons Ohio Paralysed Paresis Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Persons Physicians Physiology Positioning Attribute Prevalence Quadriplegia Recovery Recovery of Function Reporting Research Resources Role Scientist Signal Transduction Skeletal Muscle Specialist Spinal cord injury Spinal cord injury patients Stroke Synapses Testing Therapeutic Thinness Tissue Banks Training Trans-Synaptic Degeneration Universities Viral Work career career development central nervous system injury clinically relevant combat disability disability burden experience gene therapy hemiparesis in vivo motor behavior motor control motor disorder motor impairment mouse model nerve supply neurological rehabilitation neuromuscular neuromuscular system novel overexpression post stroke pre-clinical preclinical study recruit response stroke model stroke survivor therapeutic development therapeutic evaluation therapeutic target training opportunity transcriptome transmission process years lived with disability

项目摘要

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.

项目概要/摘要中枢神经系统（CNS）损伤，如中风和脊髓损伤（SCI）是导致全球残疾负担。减轻中枢神经系统损伤是研究和神经康复的核心加强恢复的策略。然而，越来越多的证据表明周围神经系统（PNS）在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 电机输出与骨骼肌功能，其中运动单位招募和放电频率调节控制。电机单元包括一个运动神经元及其支配的所有肌纤维。为了精确地控制运动，健康的肌纤维会受到一种通过单个神经肌肉接头（NMJ）的运动神经元轴突。研究表明，严重的运动单位损失中风和 SCI 后的麻痹肌，但确切的机制尚不清楚。此外，申请人最近发现中风后显着的 NMJ 重塑，包括异常的多轴突神经支配（PAI），其中 NMJ 接收多个轴突输入。 SCI 中的试验数据表明运动单位损失类似于中风，但影响 NMJ 的 SCI 仍有待探索。总而言之，该项目将探讨适应不良的 PNS 重塑在中枢神经系统损伤致残的情况下。这项工作将测试针对瘫痪 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 可塑性调节因子。在中风和脊髓损伤的小鼠模型，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力；评估运动神经元池和 NMJ 的组织病理学；采用分子定义 PAI 机制的生物学技术；并验证一种新的基因治疗方法。目标 1 将测试假设 SCI 会导致运动单位功能障碍和 NMJ 重塑，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退化是负责，但是我们假设发育介质的重新表达会诱导运动单元重叠， PAI 在电生理学上表现为虚假的运动单位损失。目标 3 将检验以下假设： BDNF 信号传导的中风减少驱动 PAI，同时通过腺相关病毒传递使 BDNF 正常化恢复 NMJ 形式和运动功能。指导的转化神经肌肉生理学培训申办者（在神经肌肉健康和治疗方面拥有丰富临床前/临床经验的神经肌肉专家）疾病）由 CNS/PNS 疾病基因治疗专家作为共同申办者进行补充，并得到以下机构的支持两名关键合作者（一名 SCI 医师科学家和一名具有 BDNF 信号传导专业知识的神经科学家）。这导师团队与俄亥俄州立大学优良的资源和环境相契合，促进新调查领域的发展并为申请人的独立做好准备。使用临床相关的研究中枢神经系统损伤后运动功能障碍的外周机制的方法，该项目将扩展对中风和 SCI 残疾的基本了解，为未来针对外周血管的治疗提供信息改变，并为学术神经学研究的职业发展提供重要的培训机会。