Recovery of Respiratory Function After Spinal Cord Injury

描述(由申请人提供)：建议的研究针对上颈髓损伤(SCI)后的可塑性和呼吸功能恢复的非常基本的问题。美国每年约有11000例新的脊髓损伤病例，有近50万人受到影响。大多数脊髓损伤是不完整的，脊髓通路有一些保留。在脊髓损伤患者中，约52%累及颈髓，在许多情况下，这会导致节律性膈神经活动障碍和横隔肌瘫痪。其中一些脊髓损伤患者必须长期接受机械通气，相关的发病率和死亡率较高。显然，了解如何在这些脊髓损伤患者中恢复节律性的膈活动是很重要的，这是拟议研究的一个关键目标。已经确定的是，对膈运动神经元的兴奋性前运动驱动主要来自同侧延髓。其结果是，在C2脊髓半横断(SH)后，同侧兴奋性输入被移除，受影响侧的节律性膈神经活动消失。然而，在SH(神经可塑性)后，存在潜在的对侧兴奋性运动前输入到膈运动神经元，这种输入可以随着时间的推移而增强，从而导致节律性膈神经活动的功能恢复。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)通过原肌球蛋白相关的激酶受体(如TrkB)在神经可塑性中发挥重要作用。我们的中心假设是，SH后节律性隔膜活动的功能恢复是通过增加隔膜运动神经元中的TrkB.FL信号来促进的。我们的长期目标是开发一种有效的治疗方法来增加膈运动神经元TrkB.FL的表达，从而促进上颈椎脊髓损伤后的功能恢复。我们提出以下五个具体目标：1)检测SH后隔膜运动神经元TrkB受体表达和/或信号减少对节律性膈神经活动功能恢复的影响；2)确定持续存在神经营养因子(长期效应)是否增加SH后隔膜运动神经元TrkB.FL的相对表达；3)确定SH后隔膜运动神经元TrkB.FL信号下游通路的变化；4)确定SH后隔膜运动神经元TrkB信号的时间依赖性变化是否介导了鞘内BDNF治疗对不同行为条件下的功能恢复的急性促进作用；5)研究胸膜内基因转移治疗是否通过增加膈运动神经元TrkB.FL的表达来促进SH后节律性膈神经活动的功能恢复。 与公共卫生相关：脊髓损伤是一个毁灭性的问题，在美国约有50万人受到影响，每年新增1.1万例。横隔肌是最重要的吸气肌，在许多脊髓损伤的病例中，它是瘫痪或严重受损的。建议的研究将为脊髓损伤后膈神经活动和隔膜功能恢复的潜在机制提供重要的新信息。

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.