Enhancing Respiratory Motor Function after Spinal Cord Injury

增强脊髓损伤后的呼吸运动功能

• 批准号: 10083760
• 负责人: Carlos B Mantilla
• 金额: $ 57.82万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083760
• 关键词: Affect; Behavior; Brain-Derived Neurotrophic Factor; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Contralateral; Coughing; Data; Dependence; Development; Fatigue; Future; Glutamates; Hypercapnia; Hypoxia; Impairment; Injury; Ipsilateral; Laboratories; Measures; Mechanical ventilation; Mediating; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Muscle; N-Methylaspartate; Nerve; Neuronal Plasticity; Paralysed; Pathway interactions; Patients; Presynaptic Terminals; Rattus; Recovery; Research; Resistance; Respiratory Diaphragm; Respiratory physiology; Role; Signal Transduction; Sneezing; Spinal; Spinal cord injury; Synapses; Time; United States; base; density; gain of function; knock-down; loss of function; mRNA Expression; mortality; neurotransmission; novel therapeutics; overexpression; postsynaptic; presynaptic; receptor; receptor expression; recruit; respiratory; small hairpin RNA; therapeutically effective; ventilation

ABSTRACT The proposed studies exploit exciting new developments in neuroplasticity to enhance recovery of ventilatory- related diaphragm muscle (DIAm) activity following cervical spinal cord injury. There are nearly 17,000 new cases of spinal cord injury in the United States each year, with around 282,000 people affected. The majority of these injuries involve the cervical spinal cord and result in significant impairment of ventilatory-related DIAm activity and an inability to maintain adequate ventilation. Long-term dependence on mechanical ventilation is associated with significant morbidity and mortality. Thus, enhancing recovery of ventilatory-related DIAm activity following cervical spinal cord injury is highly significant. Upper-cervical (C1-C3) spinal cord injury disrupts direct excitatory descending bulbospinal glutamatergic (Glu) input to phrenic motor neurons (PhMNs). Importantly, most spinal cord injuries are incomplete, thus spared descending pathways to PhMNs are an extant substrate for neuroplasticity to restore DIAm activity, either by increasing excitatory (Glu) nerve terminal density and/or by altering postsynaptic Glu receptor (NMDA NR1) expression. In the proposed studies, we will employ a well-established C2 spinal hemisection (C2SH) model of incomplete spinal cord injury in rats, in which spontaneous recovery of ventilatory-related DIAm activity occurs in a BDNF/TrkB signaling-dependent fashion. Previously, we found that C2SH impairs ventilatory-related DIAm behaviors, which require recruitment of smaller (more excitable) PhMNs comprising fatigue resistant motor units. These ventilatory-related behaviors only partially recover over time, whereas, surprisingly, there is near full recovery of higher force airway clearance behaviors, which require recruitment of larger (less excitable) PhMNs comprising more fatigable motor units. The overall hypothesis of the proposed research is that the mechanisms underlying neuroplasticity and recovery of ventilatory-related DIAm activity after C2SH depend on PhMN size (more pronounced in smaller PhMNs), are mediated by NMDA Glu neurotransmission, and are promoted by BDNF/TrkB signaling. Three specific aims are proposed: 1) To determine the effect of BDNF/TrkB signaling on Glu presynaptic terminal density at PhMNs of differing size after C2SH; 2) To determine the effect of BDNF/TrkB signaling on NMDAR expression at PhMNs of differing size after C2SH; and 3) To determine whether NMDARs underlie the effects of BDNF/TrkB signaling on recovery of ventilatory-related DIAm activity after C2SH. The results of the proposed studies will guide development of effective therapeutic approaches to enhance recovery of respiratory function in patients with incomplete spinal cord injury.

抽象的 拟议的研究利用了令人兴奋的神经可塑性的新发展，以增强通气的恢复 - 宫颈脊髓损伤后相关的隔膜肌肉（DIAM）活性。有将近17,000个新的 每年在美国脊髓损伤病例，大约有282,000人受到影响。大多数 这些损伤涉及宫颈脊髓，并导致通气相关的直径严重损害 活动和无法维持足够的通风。长期对机械通气的依赖是 与明显的发病率和死亡率相关。因此，增强了通气相关直径的恢复 宫颈脊髓损伤后的活性非常重要。上颈（C1-C3）脊髓损伤 破坏直接兴奋性降液脊髓谷氨酸能（GLU）输入到伪运动神经元（PHMN）的输入。 重要的是，大多数脊髓损伤都是不完整的，因此，普遍到达PHMN的途径是 现有的神经塑性底物可以通过增加兴奋性（GLU）神经末端来恢复DIAM活性 密度和/或通过改变突触后GLU受体（NMDA NR1）表达。在拟议的研究中，我们将 在大鼠中采用公认的C2脊柱半剖面（C2SH）模型 在BDNF/TRKB信号依赖性的呼吸相关直径活性的自发回收依赖 时尚。以前，我们发现C2SH会损害通气相关的直径行为，这需要招募 较小（更兴奋的）PHMN，包括抗疲劳电动机单元。这些与通气有关 行为仅随着时间的流逝而部分恢复，而令人惊讶的是，更高力 气道间隙行为，需要招募较大（不太兴奋的）PHMN，其中包括更多 可疲劳的电动机单元。拟议研究的总体假设是基础机制 C2SH后神经可塑性和通气相关的直径活性的恢复取决于PHMN的大小（更多 在较小的PHMN中发音），由NMDA GLU神经传递介导，并由 BDNF/TRKB信号。提出了三个具体目的：1）确定BDNF/TRKB信号的影响 C2SH后大小不同的PHMN的GLU前末端密度； 2）确定 bdnf/trkb信号传导在C2SH之后大小不同的NMDAR表达上； 3）确定 NMDAR是否是BDNF/TRKB信号传导对通气相关DIAM活性恢复的影响 C2SH之后。拟议研究的结果将指导开发有效的治疗方法 增强脊髓损伤不完全的患者呼吸功能的恢复。