Recovery of Respiratory Function After Spinal Cord Injury

脊髓损伤后呼吸功能的恢复

基本信息

批准号：
7884726
负责人：
Carlos B Mantilla
金额：
$ 59.28万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884726
关键词：
AMPA Receptors Accounting Acute Address Adverse effects Affect Behavioral Binding Sites Brain-Derived Neurotrophic Factor CREB1 gene Cell Nucleus Cervical Cervical spinal cord injury Cervical spinal cord structure Chimeric Proteins Contralateral Dependence Dominant-Negative Mutation Dose-Limiting Down-Regulation Driving neuroplasticity Environment Feedback Figs - dietary Gene Transfer Genes Glutamates Goals Horns Human Image Immunohistochemistry Impairment In Vitro Infusion procedures Injection of therapeutic agent Ipsilateral Label Lasers Length Long-Term Effects Mechanical ventilation Mediating Membrane Messenger RNA Modeling Morbidity - disease rate Motor Neurons Mus Muscle N-Methyl-D-Aspartate Receptors Nerve Growth Factor Receptors Neural Pathways Neuronal Plasticity Neurotrophic Tyrosine Kinase Receptor Type 2 Nuclear Nuclear Translocation Pain Paralysed Pathway interactions Phosphorylation Phosphotransferases Play Protein Isoforms Protein phosphatase Rattus Recovery Recovery of Function Relative (related person)Research Respiratory Diaphragm Respiratory physiology Role Series Side Signal Transduction Site Small Interfering RNA Solutions Spinal Cord Spinal cord injury Spinal cord injury patients Structure of phrenic nerve Synapses Therapeutic Uses Time Tropomyosin United States activating transcription factor 1 effective therapy extracellular laser capture microdissection mRNA Expression mortality mouse model neurotransmitter release neurotrophic factor neurotrophin 4 novel postsynaptic presynaptic protein expression public health relevance receptor receptor expression research study respiratory response transcription factor

项目摘要

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.

描述（由申请人提供）：拟议的研究解决了有关颈椎上部脊髓损伤（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11,000例新的SCI病例，有近50万人受到影响。大多数SCI的脊髓途径是不完整的。在SCI患者中，约有52％涉及宫颈脊髓，在许多情况下，这会导致节奏性肌神经活性和隔膜肌肉的瘫痪障碍。这些SCI患者中的一些必须维持长期的机械通气，并具有更高的发病率和死亡率。显然，重要的是要了解如何在这些SCI患者中恢复有节奏的PHRENIC活性，这是拟议研究的关键目标。众所周知，兴奋的前运动神经元的兴奋性驱动主要是从同侧髓质中散发出来的。结果，在C2脊髓半分裂（SH）同侧兴奋性输入后被去除，并在受影响的一侧消失了节奏的phrenic活性。然而，在SH（神经塑性）后，可以随着时间的推移加强对伪动神经元的潜在对侧兴奋性前输入，从而可以加强节奏的节奏性phrenic活性。融合的证据表明，神经营养蛋白（例如，脑衍生的神经营养因子-BDNF）通过肌球蛋白相关的激酶受体（例如TRKB）作用在神经塑性中起着重要作用。我们的中心假设是，SH后有节奏的PHRENIC活性的功能恢复会通过phrenic Motonerron中的TRKB.FL信号的增加增强。我们的长期目标是开发一种有效的疗法来增加trkb.fl在腓骨运动神经元中的表达，从而促进上颈科学后的功能恢复。我们提出以下五个具体目的：1）检查降低的TRKB受体表达和/或信号在PHRENIC运动神经元对SH后节奏性PHRENIC活性功能恢复的影响； 2）确定神经营养蛋白的持续存在（长期效应）是否会增加SH后phrenic Motonerrons中Trkb.fl的相对表达； 3）确定sh后phrenic Motoneron中trkb.fl信号传导下游途径的变化； 4）确定sH的Phrenic Motonerrons中TRKB信号传导的时间依赖性变化是否会介导鞘内BDNF治疗在不同行为条件下功能恢复的急性增强作用； 5）为确定使用脑力内化基因转移疗法在Phrenic运动神经元中增加TrkB.FL表达来增强SH后节奏性腓骨活性的功能恢复。公共卫生相关性：脊髓损伤是一个破坏性的问题，在美国影响约50万人，每年有11,000例新病例。隔膜肌肉是最重要的灵感肌肉，在许多脊髓损伤的情况下，它瘫痪或严重受损。拟议的研究将提供有关脊髓损伤后神经活性和隔膜功能的恢复基础机制的重要新信息。