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.

阻塞性肺疾病的症状，包括气道高反应性，可逆气道障碍物，胸部紧绷，呼吸困难，粘液过度分泌和coug，很大程度上是神经神经的过度和/或不适当激活气道和肺部。了解这些感觉神经在健康和疾病中激活的机制以及反射和感觉是由于它们激活而引起的，这是长期以来的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应在其神经末端的信号传导机制转导粘膜刺激。我们最近描述了一个气道粘膜中的化学感应转移途径依赖于发射机乙酰胆碱和乙酰胆碱受体（NACHRS）的烟碱亚类，以启动呼吸模式的变化，以响应于粘膜刺激。 NACHR的参与值得注意，因为它们的活动不当，并且在暴露于香烟烟雾或含尼古丁的蒸气的患者气道中过度招募 ecigarettes。该研究提案的中心假设是NACHR在转化反射引发了作用于迷走性感觉神经子集的内源性刺激物，并调节气道防御性反射在外围和中央均具有。我们还假设 NACHR因与哮喘和COPD以及吸烟有关的慢性粘膜刺激而破坏。本文提出的研究目的是：1）表征负责NACHR-的迷走神经亚型涉及阻塞性肺疾病和NACHR亚型的依赖性加剧； 2a）确定 NACHR依赖性咳嗽和其他气道防御反射的转导机制均处于外围神经末端，并在有选择性地的神经Crest C纤维的终止位点中心通过NACHR激活刺激； 2b）一旦建立了依赖NACHR的反射机制在健康动物中，我们将评估慢性尼古丁后转导机制的变化给药和过敏原引起的咳嗽过敏； 3）建立我们最近有趣的发现α7NACHR亚型依赖性抑制诱发的咳嗽通过中央作用部位，我们将确定NACHR激活对气道防御反射的CNS影响，以及这些中心调节慢性尼古丁给药和咳嗽超敏反应会改变途径。所有这些研究，我们将利用实验室独有的技术，包括单细胞记录和分子方法，反射生理记录和NACHR占用的体内成像。我们预计这些提出的研究的结果将揭示NACHR的新颖和基本作用气道和肺部慢性疾病患者的气道导致粘膜刺激。