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

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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.