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

描述(申请人提供)：哮喘和慢性阻塞性肺疾病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，以及持续的无效咳嗽和呼吸困难，这可能与肺功能不匹配。刺激伤害性感受器可以引起这些标志性症状。伤害性感受器是支配呼吸道的主要神经类型。它们主要由迷走神经传入的C-纤维和A-纤维组成。我们已经确定了呼吸道迷走神经伤害性感受器的三种非冗余亚型(一种独特的A�咳嗽感受器和两种不同类型的C纤维)。我们的长期目标是确定这些伤害性感受器亚型兴奋性背后的离子通道和机制，以及伤害性感受器亚型激活的反射后果。本提案侧重于电压门控钠通道(NAV)。NAV在动作电位的产生、传导和设定神经激活阈值方面起着至关重要的作用。有9个NAV称为NAV1-NAV9。这一建议建立在我们开创性的观察基础上，即呼吸道中的三种伤害性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，在中枢神经系统中有非常适度的表达。这使它们成为旨在使失调的伤害性感受正常化的药物的理想靶点。在过去的十年中，这些通道在疼痛神经中被识别，导致选择性NAV 1.7、1.8和1.9阻滞剂的快速药物开发。其中一些目前正在进行治疗炎症和神经病理性疼痛的临床试验。目前对这些关键离子通道在呼吸道伤害性感受器中的作用知之甚少。就它们在躯体感觉系统中的研究而言，我们的知识很大程度上是基于对背根神经节细胞体的研究，以及对痛觉的行为研究。这一建议是基于我们在组织神经末梢水平上研究每种伤害性感受器亚型的兴奋性的能力(目标1)以及在其激活引起的呼吸防御反射的水平上(目标2)。这些特性将在对照动物和动物身上进行研究，在这些动物中，我们使用创新的方法，通过基因沉默或药物作用选择性地消除NAV 1.7、1.8和1.9的表达和/或功能。我们将在基线状态以及炎症介质引起的高度兴奋状态(目标1)或呼吸道病毒感染引起的反射亢进状态(目标2)下对小鼠和豚鼠进行这项研究。这项工作将促进我们对内脏伤害性感受器终末如何在健康和疾病中调节兴奋性的基本理解。此外，该研究还将提供一个合理的框架，作为未来NAV选择性阻滞剂(已在人体使用)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。

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.