Respiratory Virus Induced Sensory Neuroplasticity

呼吸道病毒引起的感觉神经可塑性

• 批准号: 8848112
• 负责人: Bradley Joel Undem
• 金额: $ 39.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848112
• 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 therapeutics; receptor; research study; respiratory; respiratory infection virus; respiratory virus; small hairpin RNA; treatment strategy

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。对于许多人来说，这是一个自我限制的问题。对于其他人来说，这可能会导致严重的发病率。事实上，病毒感染是儿童哮喘加重的主要原因，也是COPD加重的常见原因。病毒感染也被认为是慢性干咳的主要原因，据说影响多达 10% 的人口。该提案的长期目标是更好地理解呼吸道病毒诱导的感觉神经调节所涉及的机制和介质。在目标 1 中，我们特别提出了我们的假设，并得到了初步数据的支持，即病毒感染导致迷走神经肺外 A 纤维发生表型变化，从而呈现出 C 纤维伤害感受器样表型。我们重点关注结状肺外 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，并且当它们被激活时，会导致咳嗽、反射性分泌物和支气管收缩。我们假设病毒感染从头诱导 A 纤维神经元中配体门控离子通道 TRPV1、TRPA1 和嘌呤能受体的表达，使它们对通常不会做出反应的无数刺激做出反应。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，我们通过记录气管中单个 A 神经末梢的动作电位放电，在功能水平上进一步解决这一假设，并在生理学上使用咳嗽反射作为结果。在目标 3-4 中，实验旨在解决以下假设：病毒诱导的神经可塑性的机制涉及脑源性神经营养因子 (BDNF/NT3) 和/或神经胶质细胞源性神经营养因子配体 (GFL) 分别与 TRKB 和 GFR¿ 受体相互作用。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将腺相关病毒-sh-RNA递送至结状神经节来沉默体内迷走神经感觉神经元中的基因表达来解决我们的假设。我们的多学科方法的结果应该具有内在价值，可以提供有关气道感觉神经可塑性的新知识。这些结果还将为呼吸道病毒感染复杂的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。