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Cholinergic mechanisms involved in transduction of airway defensive reflexes

胆碱能机制参与气道防御反射的转导

基本信息

批准号：
10246173
负责人：
BRENDAN J CANNING
金额：
$ 51.53万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246173
关键词：
Acetylcholine Action Potentials Acute Address Afferent Neurons Agonist Airway Disease Allergens Allergic inflammation Anatomy Animals Antitussive Agents Applications Grants Asthma Brain Stem Breathing Bronchial Spasm C Fiber Cavia Cell Nucleus Cells Cellular Structures Chest Cholinergic Receptors Chronic Chronic Disease Chronic Obstructive Airway Disease Coughing Disease Dyspnea Electronic cigarette Enzymes Epithelial Cells Esthesia Fiber Gene Expression Gene Silencing Goals Health Homeostasis Human Human Volunteers Hypersensitivity Imaging Techniques Immune Immune response Immunohistochemistry Infection Inflammatory Institution Irritants Laboratories Lung Lung diseases Maps Methods Microinjections Modeling Molecular Mucous Membrane Nerve Neural Crest Neuromuscular Junction Neurons Nicotine Nicotinic Receptors Nociception Obstructive Lung Diseases Organ Pathway interactions Patients Pattern Peripheral Peripheral Nerves Peripheral Nervous System Physiological Physiological Processes Play Positron-Emission Tomography Process Receptor Activation Reflex action Regulation Regulatory Pathway Research Research Proposals Role Sensory Signal Transduction Site Sleep Smoker Smoking Stimulus Structure of parasympathetic ganglion Sympathetic Ganglia Symptoms Synapses Synaptic Transmission System Techniques Tissues Transgenic Organisms Up-Regulation Visceral afferent nerve airway epithelium airway hyperresponsiveness airway obstruction autonomic reflex cholinergic cholinergic neuron cholinergic synapse exposure to cigarette smoke in vivo imaging irritation mucus hypersecretion nicotine vapor novel patch clamp receptor recruit respiratory respiratory reflex response sensory system visceral afferent nerve

项目摘要

The symptoms of obstructive lung diseases, which include airways hyperresponsiveness, reversible airways obstruction, chest tightness, dyspnea, mucus hypersecretion and cough, are in large part the result of an excessive and/ or inappropriate activation of the vagal afferent nerves innervating the airways and lungs. Understanding the mechanisms by which these sensory nerves are activated in health and disease and the reflexes and sensations evoked as a consequence of their activation have been longstanding goals of the research carried out in our laboratories. Visceral afferent nerves often rely on specialized chemosensory signaling mechanisms at their nerve terminals to transduce mucosal irritation. We recently described a chemosensory transduction pathway in the airways mucosa that relies on the transmitter acetylcholine and the nicotinic subclass of acetylcholine receptors (nAChRs) to initiate changes in breathing pattern in response to mucosal irritation. The involvement of nAChRs is noteworthy, as their activity is inappropriately and excessively recruited in the airways of patients exposed to cigarette smoke or the nicotine-containing vapors of eCigarettes. The central hypothesis of this research proposal is that nAChRs play essential roles in transducing reflexes initiated endogenous irritants acting on subsets of vagal sensory nerves, and modulate airway defensive reflexes both peripherally and centrally. We also hypothesize that the regulatory functions of nAChRs are corrupted by chronic mucosal irritation associated with asthma and COPD, and by smoking. Studies proposed herein aim to: 1) characterize the vagal afferent nerve subtypes responsible for nAChR- dependent exacerbations of obstructive lung diseases and the nAChR subtypes involved; 2a) determine the transduction mechanisms for nAChR-dependent coughing and other airway defensive reflexes both at the peripheral nerve terminals and centrally at the termination sites of the neural crest C-fibers that are selectively stimulated through nAChR activation; 2b) once the mechanisms for nAChR-dependent reflexes are established in healthy animals, we will evaluate changes in transduction mechanisms following chronic nicotine administration and during allergen-induced cough hypersensitivity; and 3) building upon our intriguing recent discovery of α7 nAChR subtype dependent inhibition of evoked coughing through central sites of action, we will determine the CNS effects of nAChR activation on airway defensive reflexes, and how these central regulatory pathways are altered by chronic nicotine administration and during cough hypersensitivity. For all of these studies, we will utilize techniques that are unique to our laboratories, including single cell recording and molecular approaches, reflex physiological recordings and in vivo imaging of nAChR occupancy. We anticipate that the results of these proposed studies will reveal the novel and essential roles of nAChRs in transducing mucosal irritation in the airways of patients with chronic diseases of the airways and lungs.

阻塞性肺病的症状，包括气道高反应性、可逆性气道阻塞、胸闷、呼吸困难、粘液分泌过多和咳嗽，在很大程度上是由于支配气道和肺部的迷走神经传入神经的过度和/或不当激活。了解这些感觉神经在健康和疾病中被激活的机制以及反射和由于其激活而引起的感觉一直是人类的长期目标在我们的实验室进行的研究。内脏传入神经通常依赖于专门的化学感觉其神经末梢的信号传导机制可传导粘膜刺激。我们最近描述了一个气道粘膜中的化学感应转导途径依赖于递质乙酰胆碱和乙酰胆碱受体 (nAChR) 的烟碱亚类可启动呼吸模式的变化以响应粘膜刺激。 nAChR 的参与值得注意，因为它们的活性不适当并且暴露于香烟烟雾或含尼古丁蒸气的患者的气道中过度招募电子烟。本研究提案的中心假设是 nAChR 在转导反射引发作用于迷走感觉神经亚群的内源性刺激物，并调节气道防御反射有外周性和中枢性。我们还假设，调节功能 nAChR 会因哮喘和慢性阻塞性肺病相关的慢性粘膜刺激以及吸烟而被破坏。本文提出的研究旨在：1）表征负责 nAChR- 的迷走神经传入神经亚型阻塞性肺疾病和相关 nAChR 亚型的依赖性恶化； 2a) 确定 nAChR 依赖性咳嗽和其他气道防御反射的转导机制周围神经末梢和中央神经嵴 C 纤维的终止位点选择性地通过 nAChR 激活来刺激； 2b) 一旦 nAChR 依赖性反射机制建立在健康动物中，我们将评估慢性尼古丁后转导机制的变化给药期间以及过敏原引起的咳嗽过敏期间； 3）以我们最近有趣的研究为基础发现α7 nAChR亚型依赖性通过中枢作用位点抑制诱发咳嗽，我们将确定 nAChR 激活对气道防御反射的中枢神经系统影响，以及这些中枢调节机制如何长期使用尼古丁和咳嗽过敏期间会改变通路。对于所有这些研究中，我们将利用我们实验室独有的技术，包括单细胞记录和 nAChR 占据的分子方法、反射生理记录和体内成像。我们预计这些拟议研究的结果将揭示 nAChR 在对患有慢性气道和肺部疾病的患者的气道产生粘膜刺激。