MICA_Multimodal analysis of the pathophysiology of bronchiectasis
Lead Research Organisation:
University of Cambridge
Department Name: Medicine
Abstract
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.
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.
Technical Summary
Bronchiectasis is a chronic suppurative lung disease, characterised by permanent dilatation of the bronchi and leading to persistent or repeated bacterial infections that cause progressive inflammatory lung damage and eventually respiratory failure.
While cystic fibrosis (CF), primary ciliary dyskinesia (PCD), and immunodeficiencies are known to cause bronchiectasis, the majority of cases (over 200,000 in the UK) have no known aetiology, termed 'idiopathic bronchiectasis' (IB), and currently have no licensed therapies available to treat them.
There is therefore a critical unmet need to define the pathophysiology of idiopathic bronchiectasis and thereby identify therapeutic targets.
There are currently no in vitro or in vivo models of IB, mandating a multimodal, cross-disciplinary, and multi-scale, approach to understand this condition.
Our aim therefore is to integrate genomics, single cell and spatial transcriptomics, molecular cell biology, and genetically tractable, optically transparent, functional organ models (incorporating epithelial cells, phagocytic cells, and bacteria) to define key pathways involved in the pathobiology of IB.
While cystic fibrosis (CF), primary ciliary dyskinesia (PCD), and immunodeficiencies are known to cause bronchiectasis, the majority of cases (over 200,000 in the UK) have no known aetiology, termed 'idiopathic bronchiectasis' (IB), and currently have no licensed therapies available to treat them.
There is therefore a critical unmet need to define the pathophysiology of idiopathic bronchiectasis and thereby identify therapeutic targets.
There are currently no in vitro or in vivo models of IB, mandating a multimodal, cross-disciplinary, and multi-scale, approach to understand this condition.
Our aim therefore is to integrate genomics, single cell and spatial transcriptomics, molecular cell biology, and genetically tractable, optically transparent, functional organ models (incorporating epithelial cells, phagocytic cells, and bacteria) to define key pathways involved in the pathobiology of IB.
