Chronic inflammatory lung diseases are becoming increasingly prevalent, currently affecting over 12 million people in the UK and more than 420 million people worldwide. While some of these conditions, such as chronic obstructive pulmonary disease (COPD), are triggered by environmental stimuli (e.g. tobacco smoke), others are genetic disorders, such as cystic fibrosis (CF) caused by defective epithelial ion transport. These respiratory conditions share common mechanistic and pathological features, with self-perpetuating cycles of airway damage, mucus obstruction, inflammation and infection. Despite decades of research in this area, these disorders remain difficult to treat due to disease complexity and the increasing incidence of antimicrobial resistance (AMR). There is an urgent unmet clinical need to identify innovative treatment strategies, particularly novel antimicrobials.
Traditionally, in vivo studies of inflammatory dysfunction in CF and COPD have used genetically-intractable vertebrate animal models, such as mouse, pigs and ferrets. However, such studies require significant numbers of animals, which typically experience progressive multi-organ pathology and premature death. Chronic exposure of animals to pollutants also has welfare issues as administration can be stressful. Based on publication records since 2015 (with ~1,200 papers in this area each using ~30 animals), we estimate that ~36,000 animals are currently required for this research in a 5-year period. Here, we propose to develop the invertebrate Drosophila as a novel in vivo model for target and drug discovery in chronic inflammatory lung disease. We have already established Drosophila as an invaluable model to uncover fundamental molecular insight into inflammation, infection and tissue repair. Since Drosophila express homologs of the human genes defective in CF and develop CF- and COPD-like pathologies following disruption of epithelial ion transport or cigarette smoke exposure, they represent an exciting invertebrate model to accelerate understanding of these conditions. We have developed innovative methods for non-invasive 4D imaging to explore the complex, dynamic interactions between airway damage, inflammation and infection at high spatio-temporal resolution in vivo in Drosophila models of CF and COPD. We will dissect the molecular and cellular defects underlying chronic inflammatory lung disease, with a particular focus on those pathways driving chronic inflammation and regulating airway resilience to damage. Using cutting-edge transcriptomic analysis, we will obtain gene expression signatures of airway and inflammatory cells in CF and COPD and exploit Drosophila’s unrivalled genetic tractability to perform in-depth functional studies through cell-type specific genetic perturbation. Finally, we will use our Drosophila models as preclinical platforms for large-scale screens to test innovative therapeutic strategies, including novel antimicrobials to help overcome AMR, as well as combinatorial strategies with anti-inflammatory and CFTR modulators. In parallel, we will use human cell culture and genetic epidemiology to explore links between novel candidate genes and human respiratory disease.
Our multi-disciplinary team is well-placed to maximise the 3Rs impacts of our work and engage with potential end users in academia and industry, through our international network of stakeholders (including the Medicines Discovery Catapult and CF Trust). Ultimately, by exploiting the unrivalled live-imaging, genetic tractability and rapid screening opportunities of Drosophila, we aspire to replace the use of vertebrates in exploratory in vivo experiments and help refine existing animal models. Such approaches are unrealistic in current models due to the vast number of animals required and expense of generating knockout-mice. If our 3Rs impacts are fully realised, we anticipate a 30% decrease in vertebrate experiments, representing ~10,000 mice over 5 years.