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.

摘要 拟议的研究利用了神经可塑性方面令人兴奋的新发展，以促进呼吸机能的恢复。 颈髓损伤后相关横隔肌(DIAM)活动。有近17,000个新的 美国每年都有脊髓损伤病例，大约有28.2万人受到影响。大多数人 这些损伤累及颈髓，并导致与呼吸相关的直径显著受损。 活动频繁，无法保持足够的通风。长期依赖机械通风的是 与严重的发病率和死亡率相关。因此，促进呼吸机相关直径的恢复 颈髓损伤后的活动具有非常重要的意义。上颈椎(C1-C3)脊髓损伤 阻断直接兴奋性下行球部谷氨酸(Glu)对膈运动神经元(PhMN)的传入。 重要的是，大多数脊髓损伤都是不完全的，因此没有下行通路是一种 现有的神经可塑性底物通过增加兴奋性(Glu)神经末梢来恢复DIAM的活性 密度和/或通过改变突触后谷氨酸受体(NMDANR1)的表达。在建议的研究中，我们会 采用已建立的大鼠不完全脊髓损伤的C2脊髓半横断(C2SH)模型， 在BDNF/TrkB信号依赖中，哪种呼吸相关DIAM活动发生自发恢复 时尚。此前，我们发现C2SH损害了与呼吸相关的DIAM行为，这需要重新招募 更小(更易兴奋)的PhMN，包括耐疲劳的电机单元。这些与呼吸相关的 随着时间的推移，行为只能部分恢复，而令人惊讶的是，更大的力量几乎完全恢复了 呼吸道清除行为，这需要招募更大的(不那么兴奋的)PhMN，包括更多 易疲劳的发动机部件。拟议研究的总体假设是，潜在的机制 C2SH后神经可塑性和呼吸相关DiAM活动的恢复取决于PhMN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信号转导通路。我们提出了三个具体的目标：1)确定BDNF/TrkB信号转导通路的作用 C2SH后不同大小PhMN中谷氨酸突触前终末密度的变化 BDNF/TrkB信号转导对C2SH后不同大小PhMN中NMDAR表达的影响 NMDAR是否参与BDNF/TrkB信号对呼吸机相关性DIAM活动恢复的影响 在C2SH之后。建议的研究结果将指导开发有效的治疗方法 促进不完全性脊髓损伤患者呼吸功能恢复。