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

• 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
• 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

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.

项目摘要 /摘要 中枢神经系统（CNS）损伤，例如中风和脊髓损伤（SCI） 全球残疾负担。衰减中枢神经系统损伤代表了研究和神经康复的核心 增强恢复的策略。然而，越来越多的证据证明周围神经系统（PNS）改变 中枢神经系统损伤为治疗研究提供了一个未开发的区域。 PNS将CNS电动机输出与 骨骼肌功能，运动单位募集和发射速率调节控制。电动机组成 一个运动神经元和所有肌纤维都支配了它。为了精确运动，健康的肌纤维会得到一个 通过单个神经肌肉连接（NMJ）的运动神经元轴突。研究表明，电动机单位损失 中风和SCI后的par肌，尽管确切的机制是不确定的。而且，申请人最近 中风后识别出醒目的NMJ重塑，包括异常多余的神经支配（PAI），其中NMJS 接收多个轴突输入。 SCI中的飞行员数据表明​​，运动单位损失类似于中风，但影响 NMJ处的SCI仍未开发。综上所述，该项目将询问适应不良的PNS重塑 在中枢神经系统损伤的背景下。这项工作将测试用使用 脑衍生的神经营养因子（BDNF），这是一种已知的运动神经元活性和NMJ可塑性的介体。在 申请人将纵向研究运动行为，运动单元电 - 生理学和肌肉收缩力；评估运动神经池和NMJ的组织病理学；采用分子 定义PAI机制的生物学技术；并验证一种新型的基因治疗方法。 AIM 1将测试 SCI诱导运动单元功能障碍和NMJ重塑的假设，类似于中风。 AIM 2将定义 中风引起的运动单位损失的病理生理机制；一些预测运动神经元变性是 但是，我们假设对发育介质的重新表达会导致运动单位重叠， PAI在电生理上表现为虚假运动单位损失。 AIM 3将检验以下假设。 BDNF信号传导的中风减少驱动PAI，而BDNF通过腺相关的病毒递送的标准化 还原NMJ形式和运动功能。从 赞助商（具有广泛的临床前/临床经验的神经肌肉专家 疾病）由CNS/PNS疾病中的基因治疗专家作为共同发起人的补充，并由 两个主要合作者（SCI医师科学家，以及具有BDNF信号专业知识的神经科学家）。这 指导团队与俄亥俄州立大学的出色资源和环境相吻合，以促进 新调查领域的增长并为申请人做好独立准备。使用与临床相关的 CNS受伤后，询问运动功能障碍的外围机制的方法，该项目将扩大 对中风和SCI残疾的基本理解，为未来的治疗剂提供针对周围的治疗剂 改变，并为学术神经研究中的职业发展提供关键的培训机会。