Research in detail
Accelerated ageing in airway diseases
We are investigating the cellular and molecular mechanisms of cellular senescence in COPD and the role of microRNAs in accelerating the ageing process in the lung and in the comorbidities associated with COPD, including cardiovascular disease and skeletal muscle weakness. In severe asthma, we have identified a molecular phenotype associated with ageing genes and are identifying mechanisms linking these genes to asthma severity in a subset of patients.
Abnormal innate immunity on airway diseases
We have identified a defect in phagocytosis of bacteria in macrophages of COPD patients which may be associated with bacterial colonisation of the lower airways and increased frequency of exacerbations. This defect is associated with a defect in the clearance of dead cells in the lung (efferocytosis) so that inflammation cannot be adequately resolved. We are trying to identify the molecular basis for this deficiency in order to develop a biomarker and new therapies. Similarly, in severe asthma, we have identified microbiome dysbiosis and defective macrophage phagocytosis of bacteria.
We have shown that oxidative stress is an important driving mechanism of pathophysiology in COPD and severe asthma and we are studying the pathways activated by oxidative stress and why antioxidant defence mechanisms are ineffective in these diseases. We have identified abnormal mitochondrial function and dynamics as an important source of endogenous oxidant stress in COPD and severe asthma cells and this may be treated with mitochondria-targeted antioxidants. We are also investigating the potential of stem cell therapy in reversing mitochondrial abnormalities.
Both severe asthma and COPD are characterised by poor or absent response to the anti-inflammatory effects of corticosteroids. We have defined several molecular mechanisms that contribute to this corticosteroid resistance, including decreased histone deacetylase-2 (HDAC2) in response to phosphoinositide-3-kinase (PI3K) activation, activation of p38 MAP kinase and activation of c-Jun and AP-1. This may lead to the development of new treatments that reverse corticosteroid resistance in these diseases. Analysis of the U-BIOPRED cohort is beginning to define new targets that may underlie relative steroid insensitivity.
Epigenetics in airways Disease
Genetics cannot explain all the heritability of severe asthma and COPD and it is evident that epigenetics plays a key role in disease pathophysiology. We are using various genetic and pharmacological approaches linked to big data analysis to interrogate the role of DNA methylation, histone modifications and non-coding RNAs in the function of primary cells, organoids and animal models of these diseases. We are also working with epidemiology groups to examine the effect of the exposome on DNA methylation status in asthma.
Defining phenotypes and endotypes of airway disease
We are using –omics (including genomics, genetics, proteomics and metabolomics) to differentiate different phenotypes of airway disease in order to identify different endotypes with different mechanisms which may lead to more precision in therapy in the future. We use state of the art mathematical analysis in collaboration with mathematicians and computer scientists at the Data Science Institute (DSI) to analyse the big data generated. Mathematical and organoid models of disease processes are also being developed to enable prediction of on- and off-target drug effects. Analytical techniques such as topological data analysis being used to map mouse models of airways disease onto human cohorts.
Drug delivery to the airways
We are investigating how to optimise drug delivery to the airways and particularly the peripheral airways that play an important role in airway obstruction in COPD and severe asthma. We are developing multimodal tests of small airway function to assess severe asthma and COPD to study the effects of different types of inhaler device. We are developing a 3-D lung model using lung imaging and CFD simulations to systematically study aerosol deposition patterns in human airways. We are investigating the role of m-health applications in monitoring inhaler device use and of integrated digital health platforms to support asthma patients to control their disease.
Researcher: Dr Omar Usmani
- E-health: We are developing the use of home-monitoring and mHealth systems to predict asthma control and the occurrence of asthma exacerbations, and ultimately to use these systems to determine optimal Action Points at which to intervene in order to prevent loss of control or exacerbations.
- Chronic cough: We are developing methods to study patients with chronic hypersensitivity syndrome and to set up cellular models. One of the major aims is to delineate the peripheral and central mechanisms underlying sensitisation of the cough pathways by studying neuroinflammation. This will help towards phenotyping chronic cough.
- Asthma stratification: We are engaged in stratifying asthma in order to provide the best treatment for the right patient, using as much as possible omics data with bioinformatics analyses performed at DSI. We are validating new endotypes and biomarkers. This is now impacting on patient management and are setting up studies of stratification in the testing of new treatments.