Control of Airway Nociceptor Function by Voltage-Gated Sodium Channel Subtypes

电压门控钠通道亚型对气道伤害感受器功能的控制

• 批准号: 8915739
• 负责人: BRENDAN J CANNING
• 金额: $ 52.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915739
• 关键词: Action Potentials; Address; Animals; Asthma; Biology; Bronchial Spasm; Bronchitis; C Fiber; Cavia; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical Research; Clinical Trials; Control Animal; Coughing; Development; Dinoprostone; Disease; Drug Targeting; Dyspnea; Esthesia; Fiber; Frequencies; Functional disorder; Future; Gene Silencing; Generations; Genes; Genetic; Goals; Health; Hyperalgesia; Hyperreflexia; Hypersensitivity; Inflammation; Inflammation Mediators; Injury; Ion Channel; Knock-out; Knowledge; Lead; Lung diseases; Methods; Modeling; Molecular Genetics; Mus; Myocardium; Nerve; Nerve Endings; Nerve Pain; Nervous system structure; Neural Crest; Neuraxis; Neurons; Nociception; Nociceptors; Organ; Outcome; Pain; Pattern; Pharmacologic Substance; Physiology; Play; Property; RNA Interference; Reflex action; Regulation; Relative (related person); Respiratory System; Respiratory physiology; Respiratory tract structure; Role; Seminal; Sensory; Skeletal Muscle; Sodium Channel; Spinal Ganglia; Stimulus; Symptoms; System; Testing; Time; Tissues; Transgenic Organisms; Trees; Up-Regulation; Viral; Virus; Visceral; Work; Writing; afferent nerve; airway inflammation; airway surface liquid; base; behavioral study; biophysical properties; channel blockers; design; differential expression; human disease; human subject; inflammatory neuropathic pain; innovation; man; nerve threshold; neuronal cell body; novel; patch clamp; receptor; respiratory; respiratory infection virus; respiratory virus; small hairpin RNA; somatosensory; voltage

DESCRIPTION (provided by applicant): Asthma and COPD are characterized by an over-excited sensory nervous system leading to excessive reflex bronchospasm and secretions, along with persistent unproductive coughing and dyspnea that can be unmatched to lung function. These hallmark symptoms can be evoked by stimulation of nociceptors. Nociceptors are the predominate type of nerve that innervates the airways. They comprise mainly vagal afferent C-fibers and A-fibers. We have characterized three non-redundant subtypes of vagal nociceptors in the respiratory tract (a unique A� cough receptor and two distinct types of C-fibers). Our long-range goal is to determine the ion channels and mechanisms that underlie the excitability of these nociceptor subtypes, as well as the reflex consequences of nociceptor subtype activation. The present proposal focuses on voltage-gated sodium channels (NaVs). NaVs are critically involved in action potential generation, conduction, and in setting the threshold for nerve activation. There are 9 NaVs termed NaV1-NaV9. This proposal builds on our seminal observations that the three nociceptor subtypes in the airways express almost exclusively NaV 1.7, NaV 1.8, and NaV 1.9. These channels are not present in skeletal or cardiac muscle and are very modestly expressed in the central nervous system. This renders them ideal targets for drugs aimed at normalizing dysregulated nociception. Over the past decade, these channels have been recognized in pain nerves, leading to the rapid pharmaceutical development of selective NaV 1.7, 1.8, and 1.9 blockers. Some of these are presently in clinical trials for inflammatory and neuropathic pain. There is a dearth of knowledge about the function of these pivotal ion channels in airway nociceptors. To the extent that they have been studied in the somatosensory system, our knowledge is based largely on studies at the cell bodies in the dorsal root ganglia, as well as from behavioral studies on pain sensation. This proposal is based on our ability to study the excitability of each nociceptor subtype at the level of the nerve endings in the tissue (Aim 1) and at the level of respiratory defensive reflex consequences of their activation (Aim 2). These properties will be investigated in control animals and in animals in which we employ innovative methods to selectively eliminate, via genetic silencing or pharmacologically, NaV 1.7, 1.8, and 1.9 expression and/or function. We will do this in both mice and guinea pigs at baseline states as well as during states of hyperexcitabilty caused by inflammatory mediators (Aim 1), or in hyperreflexic states caused by respiratory virus infections (Aim 2). This work will advance our basic understanding of how the excitability of visceral nociceptor terminals are regulated in health and disease. In addition, the will provide a rational framework with which to base future clinical studies with NaV selective blockers (already in man) aimed at reducing the exacerbations and suffering of those with asthma, COPD, and chronic cough.

描述（由申请人提供）：哮喘和COPD的特征是感觉神经系统过度兴奋，导致过度反射性支气管痉挛和分泌物，沿着持续性干咳和呼吸困难，可能与肺功能不匹配。这些标志性症状可以通过刺激伤害感受器诱发。伤害感受器是支配气道的主要神经类型。它们主要包括迷走传入C纤维和A纤维。我们已经描述了呼吸道迷走神经伤害感受器的三种非冗余亚型（一种独特的A咳嗽受体和两种不同类型的C纤维）。我们的长期目标是确定这些伤害感受器亚型兴奋性的离子通道和机制，以及伤害感受器亚型激活的反射后果。目前的建议集中在电压门控钠通道（NaVs）。NaV在动作电位产生、传导和设定神经激活阈值中起关键作用。有9个NaV，称为NaV 1-NaV 9。这一建议建立在我们的开创性观察基础上，即气道中的三种伤害感受器亚型几乎只表达NaV 1.7、NaV 1.8和NaV 1.9。这些通道不存在于骨骼肌或心肌中，并且在中枢神经系统中非常适度地表达。这使得它们成为旨在使失调的伤害感受正常化的药物的理想靶点。在过去的十年中，这些通道已经在疼痛神经中被认识到，导致选择性NaV 1.7、1.8和1.9阻断剂的快速药物开发。其中一些目前正在进行炎症性和神经性疼痛的临床试验。目前对这些关键离子通道在气道伤害感受器中的功能了解甚少。就它们在躯体感觉系统中的研究而言，我们的知识主要基于对背根神经节细胞体的研究，以及对疼痛感觉的行为研究。该建议基于我们在组织中神经末梢水平（目标1）和其激活的呼吸防御反射结果水平（目标2）研究每种伤害感受器亚型的兴奋性的能力。这些特性将在对照动物和动物中进行研究，在这些动物中，我们采用创新的方法，通过遗传沉默或沉默，选择性地消除NaV 1.7，1.8和1.9的表达和/或功能。我们将在小鼠和豚鼠的基线状态以及炎症介质引起的过度兴奋状态（目标1）或呼吸道病毒感染引起的反射亢进状态（目标2）中进行研究。这项工作将促进我们对健康和疾病中内脏伤害感受器末梢的兴奋性是如何调节的基本理解。此外，这将提供一个合理的框架，为未来的NaV选择性阻滞剂（已在人体内）临床研究奠定基础，旨在减少哮喘、COPD和慢性咳嗽患者的病情加重和痛苦。