Respiratory Virus Induced Sensory Neuroplasticity

呼吸道病毒引起的感觉神经可塑性

基本信息

批准号：
8701369
负责人：
Bradley Joel Undem
金额：
$ 39.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701369
关键词：
Action Potentials Address Adult Affect Afferent Neurons Antibodies Asthma Brain-Derived Neurotrophic Factor Bronchi Bronchial Spasm Bronchoconstriction C Fiber Cavia Cells Characteristics Child Chronic Chronic Obstructive Airway Disease Complex Coughing Data Dependovirus Disease Epithelium Family Fiber Functional disorder GDNF gene Gated Ion Channel Gene Expression Gene Targeting Genetic Goals Hypersensitivity Infection Inflammation Ion Channel Knowledge Lead Left Ligands Light Lung diseases Mediator of activation protein Methods Modeling Molecular Morbidity - disease rate Mucous body substance Mutation NTF3 gene NTRK2 gene Nerve Nerve Growth Factor Receptors Nervous system structure Neuroglia Neuronal Plasticity Neurons Nociceptors Nodose Ganglion Nose Oral Outcome Pathway interactions Pharyngeal structure Phenotype Physiological Population Production Purinoceptor Reflex action Research Respiratory System Respiratory tract structure Role Sensory Sensory Ganglia Signal Transduction Sneezing Sore Throat Stimulus Symptoms TRPV1 gene Time Trachea Tracheal Epithelium Viral Viral Respiratory Tract Infection Virus Virus Diseases Wheezing afferent nerve base design experience in vivo insight interdisciplinary approach member mimicry neuroregulation neurotrophic factor neurturin novel novel therapeutics public health relevance receptor research study respiratory respiratory infection virus respiratory virus small hairpin RNA treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Respiratory virus infections modulate the sensory nervous system leading to sneezing, sore throat, coughing, reflex secretions and wheezing. For many this is a self-limiting problem; for others this can progress to significant morbidity. In fac, viral infections are the leading cause of asthma exacerbations in children, and are also a common cause of COPD exacerbation. Viral infections are also thought to be a leading cause of chronic unproductive cough that is said to affect as many as 10% of the population. The long-range goal of this proposal is to develop at a better understanding of the mechanisms and mediators involved in respiratory virus-induced sensory neuromodulation. In Aim 1 we specifically address on our hypothesis, supported by preliminary data, that viral infection leads to a phenotypic change in the vagal extrapulmonary A¿ fibers such they take on a C-fiber nociceptor-like phenotype. We focus on the nodose extrapulmonary A-fibers because they terminate just beneath the epithelium in large airways (the target cell in many respiratory virus infections) and because when they are activated it leads to coughing, reflex secretions and bronchoconstriction. We hypothesize that viral infections induce, de novo, the expression of the ligand-gated ion channels TRPV1, TRPA1, and purinergic receptors, in the A-fiber neurons rendering them responsive to myriad stimuli they would ordinarily be unresponsive to. We address this hypothesis at the level of gene expression in single identified neurons. In Aim 2 we further address this hypothesis at a functional level both electrophysiologically by recording action potential discharge from single A¿ nerve terminals in the trachea, and physiologically using the cough reflex as an outcome. In Aims 3-4 experiments are designed to address the hypothesis that the mechanisms underlying the viral-induced neuroplasticity involved brain-derived neurotrophic factor (BDNF/NT3) and/or glial cell-derived neurotrophic factor ligands (GFLs) interacting with the TRKB and GFR¿ receptors, respectively. We address our hypotheses using a strategy of mimicry, pharmacological antagonism and by making use of our recently validated method to silence gene expression in vagal sensory neurons in vivo with adeno-associated virus-sh-RNAs delivered to the nodose ganglion. The results from our multidisciplinary approach should be of intrinsic value in providing new knowledge regarding sensory neuroplasticity in the airways. The results will also shed new light on the complex pathophysiology of respiratory viral infections and possibly suggest new therapeutic strategies for treatment aimed at limiting viral evoked exacerbations of asthma, COPD, and chronic cough.

描述（由申请人提供）：呼吸道病毒感染会调节感觉神经系统，导致打喷嚏、喉咙痛、咳嗽、反射性分泌物和喘息，对于其他人来说，这可能会导致严重的发病。病毒感染是儿童哮喘恶化的主要原因，也是慢性阻塞性肺病恶化的常见原因。病毒感染也被认为是慢性干咳的主要原因。据说该提案影响了多达 10% 的人群，其长期目标是更好地了解呼吸道病毒诱导的感觉神经调节的机制和介质。初步数据支持的假设是，病毒感染导致迷走神经肺外 A 发生表型变化我们关注结状肺外 A 纤维，因为它们终止于大气道上皮（许多呼吸道病毒感染的靶细胞）下方，并且因为当它们被激活时，它会产生类似 C 纤维伤害感受器的表型。我们发现病毒感染会从头诱导配体门控离子通道 TRPV1、TRPA1 和嘌呤能的表达。我们在单个已识别神经元的基因表达水平上解决了这一假设，在目标 2 中，我们在电生理学的功能水平上进一步解决了这一假设。通过记录单个 A 的动作电位放电目的 3-4 实验旨在解决病毒诱导神经可塑性的机制涉及脑源性神经营养因子 (BDNF/NT3) 和/或脑源性神经营养因子 (BDNF/NT3) 的假设。或神经胶质细胞源性神经营养因子配体 (GFL) 与 TRKB 和 GFR 相互作用¿我们使用拟态、药理学拮抗策略以及利用我们最近验证的方法通过递送至结状神经节的腺相关病毒-sh-RNA来沉默体内迷走神经感觉神经元的基因表达来解决我们的假设。我们的多学科方法的结果对于提供有关气道感觉神经可塑性的新知识应该具有内在价值，这些结果还将为呼吸道病毒感染的复杂病理生理学提供新的线索，并可能提出新的治疗策略。旨在限制病毒引起的哮喘、慢性阻塞性肺病和慢性咳嗽的恶化。