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：
9069938
负责人：
Bradley Joel Undem
金额：
$ 40.5万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069938
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 Health 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 therapeutic intervention novel therapeutics phenotypic data receptor research study respiratory infection virus respiratory virus small hairpin RNA

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（由适用提供）：呼吸道病毒感染调节感官神经系统，导致偷偷摸摸，喉咙痛，咳嗽，反射分泌和喘息。对于许多人来说，这是一个自我限制的问题。对于其他人，这可以发展到明显的发病率。在FAC中，病毒感染是儿童哮喘恶化的主要原因，也是COPD加剧的常见原因。病毒感染也被认为是慢性非生产性美洲狮的主要原因，据说会影响多达10％的人群。该提案的远程目标是更好地理解参与呼吸道病毒引起的感觉神经调节的机制和介体。在AIM 1中，我们在初步数据的支持下专门解决了我们的假设，病毒感染会导致迷走神经外肺化纤维的表型变化，使得它们对C纤维伤害感受器样表型进行。我们专注于淋巴结外A纤维，因为它们在大型气道（许多呼吸道病毒感染中的目标细胞）的上皮下方终止，因为当它们被激活时，它会导致咳嗽，反射分泌和支气管收缩。我们假设病毒感染诱导，从头诱导了配体门控离子通道TRPV1，TRPA1和嘌呤能受体的表达，在A纤维神经元中使它们对无数刺激有反应的神经元通常不会反应。我们在单个鉴定神经元中的基因表达水平上解决了这一假设。在AIM 2中，我们通过记录来自气管中单个A神经末端的动作电位排放，并实际使用咳嗽反射作为结果来进一步解决该假设。在AIMS 3-4实验中旨在解决以下假设：病毒诱导的神经可塑性的基础机制涉及脑衍生的神经营养因子（BDNF/NT3）和/或神经胶质细胞衍生的神经营养因子因子（GFL）（GFL）（GFL）与TRKB和GFR的相互作用。我们使用模仿，药物拮抗作用的策略，并利用我们最近经过验证的方法在体内沉默基因表达，并使用腺相关的病毒-SH-RNA在体内沉默的基因表达来解决我们的假设。我们多学科方法的结果在提供有关气道中感觉神经可塑性的新知识方面应该具有内在价值。结果还将为呼吸道病毒感染的复杂病理生理学提供新的启示，并可能提出用于治疗的新治疗策略，旨在限制病毒引起的哮喘，COPD和慢性咳嗽的加重。