Investigating STING as a gatekeeper of lung inflammation through the study of monogenic type I interferonopathies

间质性肺病（ILD）由一组与肺部不受控制的炎症相关的疾病组成。这会导致呼吸困难，在短时间内会逐渐恶化，并缩短生命。ILD可作为炎性疾病的一部分发生，如类风湿性关节炎或严重肺部感染。它也可以是“特发性的”，这意味着原因不明。为什么有些人发展ILD而另一些人没有的原因尚不清楚，可悲的是，可用的治疗方法非常有限，而且往往不起作用。有一个真实的需要更多地了解ILD发生背后的生物学机制，以便为受影响的人开发新的治疗方法。I型干扰素病是一组与称为I型干扰素的化学信使的不受控制的产生相关的遗传性炎症状况。在其中两种称为“婴儿期发作的STING相关血管病变”（称为SAVI）和“COPA综合征”的疾病中，肺部炎症是主要特征。这通常发生在幼儿中，肺部的炎症看起来像ILD。导致SAVI和COPA综合征的缺陷基因现在已经知道，以前的工作表明，它们会导致一种名为STING的蛋白质的活性增加，这种蛋白质与I型干扰素的产生有关。这一点很重要，因为其他一些I型干扰素病也涉及STING活性增加，但这些疾病的特征是其他身体部位（通常是大脑）的炎症，通常不涉及肺部。我认为这种差异与肺中触发STING活性的方式有关。在这个项目中，我将详细研究这个问题。研究肺部有时很棘手，因为很难知道如何在实验室中最好地研究人类肺部疾病。在这个项目中，我将访问美国哥伦比亚大学的一个实验室，他们是一项技术的世界领导者，在这项技术中，可以使用最初来自血液样本的细胞在实验室中培养称为“类器官”的人类肺组织小片。然后可以研究这些肺类器官，试图找出ILD发生的原因。我将学习这项技术，然后在爱丁堡大学的实验室里建立它。我将要求患有不同I型干扰素病的人和健康个体（对照组）捐献血液样本，我可以用它来制造肺类器官，然后我将研究不同类型的STING活动如何影响肺类器官的免疫反应。我还将研究改变STING活性的触发方式是否可以将与ILD相关的炎症促进免疫应答改变为非炎症促进免疫应答。公开可用的遗传数据集将用于研究STING在更常见类型的ILD中的作用。我还将与爱丁堡大学的其他研究人员合作，他们将分享从自愿参加正在进行的ILD研究的常见ILD患者中收集的血液和肺洗涤样本。这将使我能够研究STING在这些样本中的作用。以前已经表明，研究罕见的遗传炎症条件可以导致关于疾病如何触发的重要发现。我预计，这个项目将进一步加深我们对STING参与肺部炎症的理解，因此将有助于为罕见的I型干扰素病和其他更常见的肺部炎症形式开发新的疗法。

Interstitial lung disease (ILD) consists of a group of conditions associated with uncontrolled inflammation in the lungs. This leads to breathing difficulties which can get progressively worse over a short period of time and can shorten life. ILD can occur as part of inflammatory conditions such as rheumatoid arthritis or following severe lung infections. It can also be "idiopathic" meaning the cause is not known. The reasons behind why some people develop ILD and others do not is unclear, and sadly, available treatments are very limited and often do not work. There is a real need for greater understanding of the biology behind how ILD occurs so that new treatments can be developed for people affected.The type I interferonopathies are a group of genetic inflammatory conditions associated with uncontrolled production of a chemical messenger called type I interferon. In two of these conditions called 'STING-associated vasculopathy with onset in infancy' (known as SAVI), and 'COPA syndrome', lung inflammation is the main feature. This usually occurs in young children and the inflammation in the lungs looks like ILD. The faulty genes that cause SAVI and COPA syndrome are now known and previous work has shown that they cause an increase in the activity of a protein called STING which is involved in type I interferon production. This is important because some other type I interferonopathies also involve increased STING activity, but these are characterised by inflammation in other body parts, usually the brain, and do not normally involve the lungs. I propose that this difference is to do with the way in which the activity of STING is triggered in the lung. In this project I will study this question in detail.Researching the lung is sometimes tricky because it is difficult to know how best to study human lung disease in the laboratory. In this project I will visit a laboratory in Columbia University, USA who are world-leaders in a technique where small pieces of human lung tissue called "organoids" can be grown in the laboratory using cells that originally came from a blood sample. These lung organoids can then be studied to try to work out why ILD is occurring. I will learn this technique and then establish this in the laboratory at The University of Edinburgh. I will ask people with different type I interferonopathies and healthy individuals (controls) to donate a blood sample which I can use to make lung organoids, and then I will study how different types of STING activity affect the immune response in the lung organoids. I will also investigate if altering how STING activity is triggered can change an inflammation promoting immune response associated with ILD to a non-inflammation promoting immune response. Publicly available genetic datasets will be used to investigate a role for STING in more common types of ILD. I will also collaborate with other researchers in The University of Edinburgh who will share blood and lung washing samples collected from patients with common forms of ILD who have volunteered to be part of an ongoing ILD study. This will enable me to study the role of STING in these samples.It has been shown previously that studying rare genetic inflammatory conditions can lead to important discoveries about how diseases are triggered. I anticipate that this project will further our understanding about the involvement of STING in lung inflammation and will therefore help towards developing new therapies for the rare type I interferonopathies and for other more common forms of lung inflammation.