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: 8667815
• 负责人: BRENDAN J CANNING
• 金额: $ 55.24万
• 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/8667815
• 关键词: Action Potentials; Address; Animals; Asthma; Behavioral; 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; biophysical properties; channel blockers; design; human disease; human subject; inflammatory neuropathic pain; innovation; man; nerve threshold; neuronal cell body; novel; patch clamp; public health relevance; 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）：哮喘和慢性阻塞性肺病的特征是感觉神经系统过度兴奋，导致反射性支气管痉挛和分泌物过多，以及与肺功能不匹配的持续性干咳和呼吸困难。伤害感受器是支配气道的主要神经类型，它们主要包括迷走神经传入 C 纤维和我们已经表征了呼吸道中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其离子通道和机制。这些伤害感受器亚型的兴奋性以及伤害感受器亚型激活的反射后果是本研究重点关注的电压门控钠通道（NaV）。关键参与动作电位的产生、传导和神经激活阈值的设置 有 9 种 NaV，称为 NaV1-NaV9。该提议基于我们的开创性观察，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或心肌中，并且在中枢神经系统中表达非常适度，这使得它们成为药物的理想靶点。在过去的十年里，这些通道在疼痛神经中得到了认可，导致选择性 NaV 1.7、1.8 和 1.9 阻滞剂的药物开发迅速，其中一些目前正在进行治疗炎症和神经性疼痛的临床试验。我们对气道伤害感受器中这些关键离子通道的功能知之甚少，就体感系统中对它们的研究而言，我们的知识主要基于研究。该提议基于我们研究组织中神经末梢水平的每种伤害感受器亚型的兴奋性的能力（目标 1）和这些特性将在对照动物和我们采用创新方法通过基因沉默或药理学选择性消除 NaV 的动物中进行研究。 1.7、1.8 和 1.9 的表达和/或功能我们将在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下对小鼠和豚鼠进行此研究。 （目标 2）。这项工作将增进我们对健康和疾病中内脏伤害感受器末梢兴奋性如何调节的基本了解。一个合理的框架，作为未来 NaV 选择性阻滞剂（已在人类中进行）临床研究的基础，旨在减少哮喘、慢性阻塞性肺病和慢性咳嗽患者的病情加重和痛苦。