MICA: Defining the functional modes of action, and therapeutic potential of targeting, the free fatty acid receptor FFA4 in the lung.

哮喘和慢性阻塞性肺疾病（COPD）是影响全球50亿人的两种主要肺部疾病。仅在欧盟，每年治疗这两种疾病的费用就高达560亿欧元。虽然有许多治疗哮喘和慢性阻塞性肺病的好方法，但它们只对一小部分患者有效。例如，45%的哮喘患者仍未得到控制。另一个令人担忧的事实是，没有药物可以阻止哮喘或慢性阻塞性肺病的进展。因此，迫切需要更清楚地了解肺是如何工作的，以及如何开发可能缓解人类肺部疾病症状并预防疾病进展的药物。这个项目旨在解决这些问题。我们一直在研究肺部的一种受体蛋白，它可以被脂肪激活。这似乎有点奇怪，因为激活这种受体蛋白的脂肪来自我们的饮食。尽管如此，被称为游离脂肪酸4 （FFA4）的受体蛋白，当被类似药物的小分子激活时，会导致肺部气道周围的肌肉松弛。这种放松反应打开气道，让更多的空气进出肺部。我们已经证明，激活FFA4的药物可以改善哮喘和COPD小鼠模型的肺功能。这些初步数据表明，制造激活FFA4的药物可能是治疗哮喘和慢性阻塞性肺病的好方法。这里提出的拨款将使用疾病的小鼠模型以及患有哮喘和慢性阻塞性肺病的人类患者的组织来询问FFA4是否是开发人类气道疾病药物的良好靶点。为了实现这一目标，我们不仅利用我们在药物作用机制（药理学）方面的经验，而且还召集了一个包括呼吸内科医生和制药公司Astra Zeneca在内的期望团队。因此，有了这些综合的专业知识和优秀的初步数据，再加上强大的基因工程小鼠模型，我们希望达到本基金提出的目标。

Asthma and chronic obstructive pulmonary disorder (COPD) are two major lung diseases affecting >500 million people worldwide. Treating these two diseases in the European Union alone costs >56 billion EUROs per annum. Although there are a number of good treatments for both asthma and COPD, these are only effective in a sub-group of patients. For example, 45% of asthmatics remain uncontrolled. An additional alarming fact is that there are no drugs that can stop the progression of either asthma or COPD. There is therefore an urgent need to develop a clearer understanding of how the lung works and how to develop drugs that might relieve symptoms of human lung disease as well as prevent the progression of disease. This project aims to address these issues. We have been working on a receptor protein in the lung that is activated by fats. This seems a little strange since the fats that activate this receptor protein come from our diet. Despite this, the receptor protein, called free fatty acid 4 (FFA4), when activated by small drug-like molecules, results in relaxation of muscle that surrounds the airways in the lung. This relaxation response opens the airways allowing more air to flow in an out of the lung. We have showed that drugs that activate FFA4 improve the function of the lungs in mouse models of asthma and COPD. These preliminary data suggest that making drugs that activate FFA4 might be a good way of treating asthma and COPD. The grant presented here will use mouse models of disease as well as tissue from human patients suffering from asthma and COPD to ask the question whether FFA4 is a good target for the development of drugs for human airway disease. To achieve this aim we are not only drawing on our experience of the mechanisms of drug action (pharmacology) but we have also pulled together a team of expects that includes respiratory medical doctors and the drug company Astra Zeneca. Thus, with this combined expertise and excellent preliminary data, together with powerful genetically engineered mouse models we hope to reach the objectives presented in this grant.