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Underlying mechanisms of asthma

In order to develop better treatments for asthma and stop asthma attacks, we first need to fully understand what asthma is and what causes it, down to the way that molecules work in our lungs.

Researchers at the Centre working in this area will investigate the immune system and how it may be different in people with asthma; what is different in very young children who wheeze and then go on to develop asthma, versus those who wheeze but then don't develop it; understanding what our genes may tell us about the risk of developing asthma, as what those genes do can tell us about the development of the condition; and many other varied areas.

 

See the Centre structure for the full list of researchers supporting each research theme.

 

Chung and Adcock will work within the UBIOPRED European consortium, using clinical and “omics” approaches to define mechanisms of severe asthma and generate “fingerprints” that define paediatric and adult asthma types. Chung will focus on the role of airway smooth muscle and the effects of oxidant stress on muscle function, including the energetics of airway smooth muscle function.

Lloyd, Bush and Saglani, will study underlying mechanisms that contribute to development of preschool wheeze.

Lloyd will examine interactions of innate immune cells (ILCs, alveolar macrophages) with epithelial cells in paediatric and adult asthmatics and mouse models, focusing on the role of IL-10 and TGFβ using tissue-selective mutant mice.

Lord will investigate T and dendritic cell biology in mucosal protection and disease. Lord’s diagnostic test for human regulatory T-cell function provides an important investigative tool for collaboration in clinical studies of immunomodulation in asthma, to promote immunological tolerance to allergen.

Pease will study the complexity of leukocyte recruitment and molecular interactions between structural cells, focusing on the chemokine CXCL17, which appears important for lung macrophage recruitment via the orphan receptor GPR35. The chemokine receptor CCR4 is also a focus as CCR4 is involved in recruitment of Th2 cells/T-regs and activation of lung epithelial cells.

Page will investigate interaction between platelets and inflammatory cells/airway smooth muscle and the signalling mechanisms underlying these interactions, as they potentially provide novel targets for anti-inflammatory drugs to target airway remodelling.

Cookson and Moffatt will extend their genetic association work through meta-analysis of GWAS (genome-wide association studies) through the global Translational Asthma Genetics Consortium. They will explore (with Zhang, Lloyd and Dean) through in vitro and in vivo experimental approaches the function of asthma genes (ORMDL3, IL-33, IL-18L1R, TSLP, SMAD3) that have been identified through GWAS.

Lavender will collaborate widely (Johnston, Edwards, Lord, Corrigan, Hawrylowicz), to exploit the large datasets generated on transcriptional gene profiles and chromatin organisation in asthma-relevant cell types, including primary bronchial epithelial cells and T cells in virus-induced asthma exacerbations, and airway smooth muscle cells and T cells to identify chromatin remodelling enzymes mobilized by vitamin D/glucocorticoid treatment and their targets. Cells derived from steroid-resistant patients will determine whether resistance has a greater influence on some genes than others, and discover the mechanisms of these effects.

With the MRC Social, Genetic and Developmental Psychiatry Centre, KCL, Lavender and Corrigan are conducting tissue sampling of a cohort of monozygotic twins from the Environmental Risk 18yr longitudinal study. They will investigate whether differential DNA methylation in twins discordant for asthma can be linked to onset or to remission from asthma as twins pass through adolescence.