MICA: Determining the therapeutic potential of targeting the free fatty acid receptors FFA1 and FFA4 in human lung inflammatory disease

哮喘是一种慢性肺部炎症性疾病，影响到全世界30亿人，造成大量发病率，并对卫生服务造成相当大的成本。尽管目前的治疗方法有效，但仍有45%的哮喘患者无法控制病情。在这里，我们建议研究一种治疗哮喘的新方法，通过增加药物来激活我们发现存在于人类肺部的受体蛋白，当受体蛋白被激活时，可以减少炎症，放松气道，让更多的空气进出肺部。这些受体蛋白通常会被脂肪酸激活，比如我们饮食中的omega-3脂肪酸。有些令人惊讶的是，对膳食脂肪酸有反应的受体蛋白存在于我们的肺部，但我们发现事实确实如此。我们还发现，激活这些受体蛋白，称为FFA1和FFA4，可以缓解我们已经建立的小鼠疾病模型中与炎症性肺病相关的许多症状。在这里，我们将与我们的临床同事一起工作，他们可以获得正常的人和患病的肺样本。除了利用我们在炎症性肺病小鼠模型上的专业知识进行的其他研究外，我们还将评估制造激活FFA1和FFA4的药物是否有可能缓解哮喘等肺部疾病的症状和减少炎症。

Asthma is a chronic lung inflammatory disease that affects >300 million people worldwide, causing substantial morbidity and exacting a considerable cost to health services. Despite the effectiveness of current therapies still ~45% of asthmatics remain uncontrolled. Here we propose to investigate a novel way of treating asthma by raising drugs that activate receptor proteins that we have found are present in human lungs and that when activated can reduce inflammation and relax the airways allowing more air to get in and out of the lungs. These receptor proteins are normally activated by fatty acids such as omega-3 fatty acids that are found in our diet. It is somewhat surprising that receptor proteins that respond to dietary fatty acids are present in our lungs but we have found that this is indeed the case. We have also found that activation of these receptor proteins, called FFA1 and FFA4, can relieve many of the symptoms associated with inflammatory lung disease in mouse disease models that we have established. Here we will work together with our clinical colleagues who have access to normal human and diseased lung samples. Alongside additional studies that will take advantage of our expertise in mouse models of inflammatory lung disease we will assess if making drugs that activate FFA1 and FFA4 might potentially relieve symptoms and reduce inflammation in lung diseases such as asthma.