MICA: Investigation into the mechanisms that drive cough in health and disease

咳嗽是一种反射行为，由刺激呼吸道内层的感觉神经开始，呼吸道是我们用来呼吸的管道。当一个人咳嗽时，会有一次短暂的吸气，喉咙(喉咙)会瞬间关闭。用于呼吸的腹肌和胸肌收缩，当喉咙重新打开时，这反过来又增加了将空气排出肺部所需的压力。咳嗽是一种反射机制，有助于清除呼吸道中的异物和分泌物。然而，它也可能是许多炎症性呼吸道疾病的第一个也是最持续的症状，包括哮喘、COPD、病毒后感染、肺纤维化、支气管扩张和咳嗽，当原因无法确定时也可能出现。在这些情况下，咳嗽可能会表现为一种虚弱的症状，并可能以多种方式对患者的生活质量产生不利影响，例如，导致疲惫、自我意识、失眠、马力不足、肌肉骨骼疼痛、出汗、尿失禁，在严重情况下，患者可能会因过度咳嗽而折断肋骨。尽管有这些事实，咳嗽是一个很大程度上被忽视的研究领域，并且缺乏新的止咳药物。治疗选择有限，最近的荟萃分析得出结论，非处方药(OTC)治疗无效，而且越来越多的人关注儿童使用非处方药。了解引发咳嗽的机制将发现新的治疗目标，这将对患者的生活质量和相关医疗成本的降低产生重大影响。咳嗽反射是由呼吸道感觉神经的激活引起的。我们假设抑制感觉神经活动的药物也会抑制咳嗽反射。在这项建议中，我们描述了来自我们实验室的临床前数据，来自科学文献的呼吸系统疾病的遗传关联数据，以及我们来自临床研究的数据，这些数据表明某些蛋白质或离子通道称为瞬时受体电位(Trp)通道，是咳嗽反射的主控制器。有许多这样的通道在呼吸道感觉神经中表达，因此在这个项目中，我们将在分离的神经实验(使用动物和人体组织)和咳嗽的动物模型中使用药理学(阻断这些靶点的工具化合物)或转基因小鼠(没有每种TRP通道)来评估它们的重要性。我们将研究它们在正常情况下咳嗽反应中的作用，然后在配置为类似哮喘相关咳嗽、病毒后咳嗽和慢性阻塞性肺疾病(COPD)的模型中。最后，我们将评估这些渠道在表现出不同病因的慢性咳嗽患者中的作用(例如。这些研究的目的是确定可能的新药物靶点，作为药物发现计划的起点，以寻找新的咳嗽疗法来治疗这种令人衰弱的症状。我们希望从这笔拨款中获得的另一项成果是，确定我们用来研究这一假说的各种动物模型系统是否真的代表了人类咳嗽，以及用于测试疗法的系统是否可以预测患者的止咳活性。

Coughing is a reflex action started by stimulation of sensory nerves in the lining of the respiratory passages which are the tubes we use to breathe. When a person coughs, there is a short intake of breath and the larynx (the voice box) closes momentarily. The abdominal and chest muscles used for breathing contract, which in turn increases the pressure needed to drive air out the lungs when the larynx re-opens. Cough is a reflex mechanism that helps clear foreign material and secretions from the airways. However, it may also be the first and most persistent symptom of many inflammatory airways diseases, including asthma, COPD, post viral infections, pulmonary fibrosis, bronchiectasis and cough can also be present when a cause cannot be identified. In these situations cough may present as a debilitating symptom and can adversely affect the quality of a patient's life in multiple ways for example by causing exhaustion, self consciousness, insomnia, horseness, musculoskeletal pain, sweating, urinary incontinence and in severe cases patients can break ribs through excessive coughing. Despite these facts, cough is a largely ignored research area and novel anti-tussive agents are lacking. Treatment options are limited and recent meta-analysis concluded that over the counter (OTC) remedies are ineffective plus there is increasing concern about their use in children. Understanding the mechanisms involved in initiating cough will uncover novel therapeutic targets which will impact significantly on patient quality of life and a reduction in associated healthcare costs. The cough reflex is initiated by activation of airway sensory afferent nerves. We hypothesize that agents that inhibit sensory nerve activity will also inhibit the cough reflex. In this proposal we describe pre-clinical data from our laboratory, genetic association data in respiratory disease from the scientific literature and our data from clinical studies implicating certain proteins or ion channels called Transient Receptor Potential (TRP) channels as 'master controllers' of the cough reflex. There are a number of these channels that are expressed in airway sensory nerves and so in this project we will be evaluating their importance using pharmacology (tool compounds that block these targets) or genetically modified mice (which are bred without each of the TRP channels) in isolated nerve experiments (using animal and human tissue) and in animal models of cough. We will investigate their role in the cough response under normal conditions and then in models which are configured to resemble asthma related cough, post-viral cough and that associated with chronic obstructive pulmonary disease (COPD). Finally we will evaluate the role of these channels in patients that demonstrate chronic cough of different aeitiologies (eg. Asthma, COPD, smokers, post-viral, and chronic cough of no known cause).The aim of these studies is to identify possible novel drug targets which can be used as starting points for drug discovery programmes to find novel cough therapies to treat this debilitating symptom. Another output from this grant that we hope to achieve is to establish if the various animal model systems we use to investigate this hypothesis actually represent the human cough and that the systems used to test therapeutics are predictive of anti-tussive activity in patients.