Respiratory Virus Induced Sensory Neuroplasticity

描述（由申请方提供）：呼吸道病毒感染调节感觉神经系统，导致打喷嚏、咽喉痛、咳嗽、反射性分泌物和喘息。对许多人来说，这是一个自我限制的问题;对其他人来说，这可能会发展到严重的发病率。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，据说影响多达10%的人口。这项建议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的机制和介质。在目标1中，我们特别强调了我们的假设，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？纤维的表型变化，使它们呈现C纤维伤害感受器样表型。我们专注于结节性肺外A纤维，因为它们终止于大气道上皮细胞下方（许多呼吸道病毒感染的靶细胞），并且因为当它们被激活时，它会导致咳嗽，反射分泌物和支气管收缩。我们假设，病毒感染诱导，从头，配体门控离子通道TRPV 1，TRPA 1和嘌呤能受体的表达，在A-纤维神经元，使他们响应无数的刺激，他们通常是无反应的。我们解决这个假设的基因表达水平在单个识别的神经元。在目的2中，我们进一步在功能水平上通过记录气管中单个A？神经末梢的动作电位放电和生理学上使用咳嗽反射作为结果来解决这一假设。在目的3-4中，设计实验以解决病毒诱导的神经可塑性的潜在机制涉及脑源性神经营养因子（BDNF/NT 3）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受体相互作用的假设。我们解决我们的假设使用的策略模仿，药理学拮抗作用，并利用我们最近验证的方法沉默基因表达的迷走神经感觉神经元在体内与腺相关病毒-sh-RNA传递到结状神经节。从我们的多学科方法的结果应该是内在的价值，在提供新的知识，在气道感觉神经可塑性。研究结果还将揭示呼吸道病毒感染的复杂病理生理学，并可能提出新的治疗策略，旨在限制病毒诱发的哮喘、COPD和慢性咳嗽加重。

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.