Recovery of Respiratory Function After Spinal Cord Injury

描述（由申请人提供）：拟定的研究解决了关于上颈脊髓损伤（SCI）后呼吸功能可塑性和恢复的非常基本的问题。美国每年约有11，000例新的SCI病例，近50万人受到影响。大多数SCI是不完全的，脊髓通路有一些保留。在SCI患者中，约52%涉及颈脊髓，在许多情况下，这会导致节律性膈神经活动受损和膈肌麻痹。其中一些SCI患者必须长期维持机械通气，相关的发病率和死亡率较高。很明显，重要的是要了解如何在这些SCI患者中恢复有节奏的膈神经活动，这是拟议研究的一个关键目标。膈运动神经元的兴奋性前运动驱动主要来自同侧延髓。结果，C2脊髓半切（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，有一个潜在的对侧兴奋性运动前输入到膈运动神经元，可以加强SH（神经可塑性）后的时间，导致功能恢复的节律性膈活动。越来越多的证据表明，神经营养因子（例如，脑源性神经营养因子- BDNF）通过原肌球蛋白相关激酶受体（例如，TrkB）在神经可塑性中起重要作用。我们的中心假设是，功能恢复的节奏膈活动后，SH是通过增加TrkB增强。FL信号在膈运动神经元。我们的长期目标是开发一种有效的治疗方法来增加TrkB.FL在膈运动神经元中的表达，从而促进上颈脊髓损伤后的功能恢复。我们提出了以下五个具体目标：1）研究减少的TrkB受体表达和/或膈运动神经元信号对SH后节律性膈活动功能恢复的影响; 2）确定神经营养因子的持续存在是否会影响SH后膈运动神经元的功能恢复。（远期效应）增加SH后膈运动神经元TrkB.FL的相对表达; 3）观察SH后膈运动神经元TrkB.FL信号下游通路的变化; 4）为了确定是否时间依赖性变化TrkB信号在膈运动神经元后，SH介导鞘内注射BDNF对不同行为条件下功能恢复的急性增强作用;以及5）确定是否通过使用胸膜内施用的基因转移疗法增加膈运动神经元中TrkB.FL表达来增强SH后节律性膈活动的功能恢复。

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.