MICA_Multimodal analysis of the pathophysiology of bronchiectasis

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Bronchiectasis is a disease that damages the lungs because of constant or recurrent inflammation. People with bronchiectasis will continuously produce phlegm or mucus from their chest (termed 'sputum'), as a consequence of persistent infection with bacteria and the inflammation this causes. While there are some known causes of bronchiectasis (such as cystic fibrosis, where the sputum is very sticking and cannot be brought up, or Primary ciliary dyskinesia, where there hairs the coat the inside of the airways don't work and cannot move the sputum), the majority of the 200,000 or more people who suffer with bronchiectasis in the UK have no known cause for there illness, which is referred to as 'idiopathic bronchiectasis'. There are currently no licensed medicines for this condition and, as a consequence, treatment of affected individuals is based around antibiotic treatment and physiotherapy (to clear the sputum). Patients will therefore often suffer from repeated episodes of clinical deterioration (requiring antibiotic treatment at home or in hospital), severe fatigue, and worsening breathlessness as the lung damage progresses over time. We currently do not understand what causes the development of bronchiectasis or what pathways are involved in the inflammation, and we do not have a good model system to test new drugs for this disease. Our aim therefore is to combine genetic analysis of a number of different DNA collections of people with bronchiectasis (and related conditions such as persistent cough or bronchitis) with artificial intellegence-based prediction of the effect of DNA variations on the way cells behave, in order to draw up a list of genes that may increase the risk of developing idiopathic bronchiectasis. At the same time, we will look at samples taken from patients with bronchiectasis (and healthy people of the same age) to look at the response of individual cells to stimuli and thus begin to understand the types of inflammation (and their potential causes) in bronchiectasis. We will then combine the findings of these two different approaches to create a model of how bronchiectasis is caused ad then test our ideas looking at the effect of introducing particular DNA variations (using gene editing) and the effect of particular types of inflammatory insults, on the behaviour of particular cell types in the lab. Finally we will try to re-create the lung environment in the lab by using a system where we grow all the important cells together and study how they interact with each other and with bacteria. We can then add particular inflammatory insults or introduce DNA variations we see in patients to understand how the lung might respond to them. We expect that this 'lung-on-a-chip' model will provide an very useful tool to understand why bronchiectasis occurs and to discover new treatments.