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

间质性肺病(ILD)是一组与肺部炎症失控有关的疾病。这会导致呼吸困难，在短时间内会变得越来越严重，并可能缩短生命。ILD可作为炎症条件的一部分，如类风湿性关节炎或严重的肺部感染。它也可以是“特发性的”，意思是病因不明。一些人患上ILD而另一些人不会的原因尚不清楚，可悲的是，可用的治疗方法非常有限，而且往往不起作用。确实需要更多地了解ILD发生背后的生物学原理，以便为受影响的人开发新的治疗方法。I型干扰素病是一组遗传性炎症条件，与一种名为I型干扰素的化学信使的不受控制的产生有关。在其中两种情况中，肺部炎症是主要特征，这两种情况被称为“婴儿时期起病的刺痛相关性血管病变”(称为SAVI)和“COPA综合征”。这通常发生在年幼的儿童，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为人所知，之前的研究表明，它们会导致一种名为STING的蛋白质活性增加，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型干扰素病也涉及刺痛活动增加，但这些疾病的特征是身体其他部位的炎症，通常是大脑，通常不涉及肺部。我认为这种差异与刺痛在肺中被触发的方式有关。在这个项目中，我将详细研究这个问题。研究肺部有时是很棘手的，因为很难知道如何在实验室里最好地研究人类肺部疾病。在这个项目中，我将参观美国哥伦比亚大学的一个实验室，他们在一项技术上处于世界领先地位，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出被称为“类器官”的人类肺组织小块。然后可以对这些肺器官进行研究，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建立这项技术。我会让患有不同I型干扰素病的人和健康人(对照组)捐献一份血液样本，用来制造肺器官，然后我将研究不同类型的叮咬活动如何影响肺器官中的免疫反应。我还将研究改变刺痛活动的触发方式是否可以将与ILD相关的促进炎症免疫反应改变为非炎症促进免疫反应。公开可用的基因数据集将被用来研究刺痛在更常见的ILD类型中的作用。我还将与爱丁堡大学的其他研究人员合作，他们将分享从常见形式的ILD患者身上收集的血液和肺冲洗样本，这些患者自愿参加正在进行的ILD研究。这将使我能够研究刺痛在这些样本中的作用。以前已经表明，研究罕见的遗传性炎症条件可以导致关于疾病是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在肺部炎症中的作用的了解，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.