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

咳嗽是一种反射性的动作，它是通过刺激我们用来呼吸的管道--呼吸道内壁的感觉神经而开始的。当一个人咳嗽时，有一个短的呼吸和喉（声音盒）关闭瞬间。用于呼吸的腹部和胸部肌肉收缩，这反过来又增加了当喉部重新打开时将空气排出肺部所需的压力。咳嗽是一种反射机制，有助于清除气道中的异物和分泌物。然而，它也可能是许多炎性气道疾病的第一个和最持久的症状，包括哮喘，COPD，病毒感染后，肺纤维化，支气管扩张和咳嗽也可能存在时，原因无法确定。在这些情况下，咳嗽可能表现为使人衰弱的症状，并且可能以多种方式对患者的生活质量产生不利影响，例如通过引起疲惫、自我意识、失眠、骑马、肌肉骨骼疼痛、出汗、尿失禁，并且在严重的情况下，患者可能通过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，缺乏新的止咳药。治疗选择是有限的，最近的荟萃分析得出结论，非处方药（OTC）的补救措施是无效的，加上越来越多的关注他们在儿童中的使用。了解引发咳嗽的机制将发现新的治疗靶点，这将对患者的生活质量产生重大影响，并降低相关的医疗费用。咳嗽反射由气道感觉传入神经的激活启动。我们假设抑制感觉神经活动的药物也会抑制咳嗽反射。在本提案中，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来自临床研究的数据，这些数据涉及称为瞬时受体电位（TRP）通道的某些蛋白质或离子通道作为咳嗽反射的“主控制器”。在气道感觉神经中表达了许多这样的通道，因此在本项目中，我们将在隔离神经实验（使用动物和人体组织）和咳嗽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（在没有每个TRP通道的情况下繁殖）来评估它们的重要性。我们将研究它们在正常条件下的咳嗽反应中的作用，然后在模型中，这些模型被配置为类似于哮喘相关的咳嗽、病毒感染后咳嗽和与慢性阻塞性肺疾病（COPD）相关的咳嗽。最后，我们将评估这些通道在不同病因的慢性咳嗽患者中的作用（例如：哮喘、COPD、吸烟者、病毒感染后和不明原因的慢性咳嗽）。这些研究的目的是确定可能的新型药物靶点，这些靶点可用作药物发现计划的起点，以找到治疗这种使人衰弱的症状的新型咳嗽疗法。我们希望实现的这项资助的另一个成果是确定我们用于研究这一假设的各种动物模型系统是否真的代表了人类咳嗽，以及用于测试治疗方法的系统是否能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.