Recovery of Respiratory Function After Spinal Cord Injury

描述（由申请人提供）：拟议的研究解决关于上颈脊髓损伤（SCI）后呼吸功能的可塑性和恢复的非常基本的问题。美国每年大约有1.1万例脊髓损伤新病例，近50万人受到影响。大多数脊髓损伤是不完整的，有一些脊髓通路的保留。在SCI患者中，约52%涉及颈脊髓，在许多情况下，这导致膈神经节律性活动受损和膈肌瘫痪。其中一些脊髓损伤患者必须维持长期机械通气，相关的发病率和死亡率较高。显然，了解这些脊髓损伤患者如何恢复有节奏的膈活动是很重要的，这也是本研究的关键目标。已证实，膈运动神经元的兴奋性运动前驱动主要来自同侧髓质。结果，在C2脊髓半切（SH）后，同侧兴奋性输入被移除，受累侧节律性膈活动消失。然而，对膈运动神经元存在潜在的对侧兴奋性运动前输入，该输入在SH（神经可塑性）后随着时间的推移而增强，导致膈节律性活动的功能恢复。越来越多的证据表明，神经营养因子（如脑源性神经营养因子- BDNF）通过原肌球蛋白相关激酶受体（如TrkB）发挥作用，在神经可塑性中发挥重要作用。我们的中心假设是，SH后节律性膈活动的功能恢复是通过TrkB的增加而增强的。膈运动神经元中的FL信号。我们的长期目标是开发一种有效的治疗方法来增加TrkB。膈运动神经元中FL表达促进上颈脊髓损伤后功能恢复。我们提出以下五个具体目标：1)研究颅运动神经元中TrkB受体表达和/或信号传导减少对SH后节律性颅活动功能恢复的影响；2)确定神经营养因子的持续存在（长期效应）是否会增加TrkB的相对表达。SH后膈运动神经元中的FL；3)确定TrkB下游通路的变化。SH后膈运动神经元的FL信号传导4)确定膈运动神经元TrkB信号在sh后的时间依赖性变化是否介导鞘内BDNF治疗在不同行为条件下对功能恢复的急性增强作用；5)确定SH后节律性膈活动的功能恢复是否通过增加TrkB而增强。利用胸膜内基因转移疗法研究FL在膈运动神经元中的表达。

DESCRIPTION (provided by applicant): The proposed studies address very basic questions regarding plasticity and recovery of respiratory function following upper cervical spinal cord injury (SCI). There are about 11,000 new cases of SCI in the United States each year, with nearly 500,000 people affected. Most SCI's are incomplete with some sparing of spinal cord pathways. Among SCI patients, about 52% involve the cervical spinal cord and in many cases this results in impairment of rhythmic phrenic nerve activity and paralysis of the diaphragm muscle. Some of these SCI patients must be maintained on long-term mechanical ventilation, with associated higher morbidity and mortality rates. Clearly, it is important to understand how rhythmic phrenic activity can be restored in these SCI patients and this is a key objective of the proposed research. It is well established that excitatory premotor drive to phrenic motoneurons emanates predominantly from the ipsilateral medulla. As a result, after C2 spinal cord hemisection (SH) ipsilateral excitatory input is removed and rhythmic phrenic activity disappears on the affected side. However, there is a latent contralateral excitatory premotor input to phrenic motoneurons that can be strengthened with time after SH (neuroplasticity) leading to functional recovery of rhythmic phrenic activity. Converging evidence suggests that neurotrophins (e.g., brain- derived neurotrophic factor - BDNF) acting through tropomyosin related kinase receptors (e.g., TrkB) play an important role in neuroplasticity. Our central hypothesis is that functional recovery of rhythmic phrenic activity after SH is enhanced by an increase in TrkB.FL signaling in phrenic motoneurons. Our long-term goal is to develop an effective therapy to increase TrkB.FL expression in phrenic motoneurons and thereby promote functional recovery after upper cervical SCI. We propose the following five specific aims: 1) To examine the impact of reduced TrkB receptor expression and/or signaling in phrenic motoneurons on functional recovery of rhythmic phrenic activity after SH; 2) To determine whether the continuing presence of neurotrophins (long-term effect) increases the relative expression of TrkB.FL in phrenic motoneurons after SH; 3) To determine changes in downstream pathways of TrkB.FL signaling in phrenic motoneurons after SH; 4) To determine whether time-dependent changes in TrkB signaling in phrenic motoneurons post-SH mediate the acute enhancing effect of intrathecal BDNF treatment on functional recovery during different behavioral conditions; and, 5) To determine whether functional recovery of rhythmic phrenic activity after SH is enhanced by increasing TrkB.FL expression in phrenic motoneurons using intrapleurally-administered gene transfer therapy. PUBLIC HEALTH RELEVANCE: Spinal cord injury is a devastating problem that affects about 500,000 people in the United States, with 11,000 new cases each year. The diaphragm muscle is the most important inspiratory muscle and it is paralyzed or seriously impaired in many cases of spinal cord injury. The proposed studies will provide important new information regarding the mechanisms underlying recovery of phrenic nerve activity and diaphragm function following spinal cord injury.