The Role of ADAM33 in the Origin and Progression of Asthma

Lead Research Organisation: University of Southampton
Department Name: Inflammation Infection and Repair

Abstract

We are investigating how and why disease-related differences in the asthma gene, ADAM33, lead to airway ‘twitchiness’ This characteristic feature of asthma is caused by airways that narrow too much and too easily in response to harmless stimuli, leading to typical symptoms of wheeze, shortness of breath and cough. Our discovery of ADAM33 came from a five year collaborative genetic study, where we found that small changes in the ADAM33 gene occurred in people with asthma and these changes were particularly associated with the degree of airway ‘twitchiness’. Although inflammation is an important component of asthma, it has recently been shown that an alteration in the structure (remodelling) of the airways is also important. As ADAM33 appears to act in the structural cells, rather than in inflammatory cells, we predict that ADAM33 causes airway remodelling. If we are correct, this offers the potential for development of new therapies distinct from those such as steroids that damp down the inflammatory response. By targeting the function of a gene close to the origin of asthma, this should make a major impact on our understanding of the factors that underlie this common disease and enable design of better prevention and intervention strategies.

Technical Summary

Although asthma is characterised by Th-2 type inflammation, the important clinical phenotypes of chronic and severe disease refractory to corticosteroids involve additional activation of the epithelial mesenchymal trophic unit (EMTU) linked to persistent bronchial hyperresponsiveness (BHR) and airway wall remodelling. With our discovery of ADAM33 as a novel asthma susceptibility gene closely associated with BHR and fixed airflow obstruction (bronchodilator?resistant lung function), we hypothesise that genetic variation in this gene has more than one consequence by influencing: (a) BHR through effects on smooth muscle differentiation and contractility and (b) fixed airflow obstruction through effects on ECM deposition by airway (myo)fibroblasts and smooth muscle cells. Recognizing the degree of linkage disequilibrium and the extent of polymorphic variation in the ADAM33 gene, we will use expression-based approaches to analyse its role in chronic asthma. This is absolutely dependent on access to polarised groups of well phenotyped volunteers, tissue sampling to provide ADAM33 expressing cells, and molecular genetic approaches to investigate ADAM33 gene spatial disposition, regulation and function.
Specifically, we will:
(i) Culture myofibroblasts and smooth muscle cells from bronchial biopsies of volunteers with chronic corticosteroid refractory asthma and appropriate controls to a) analyse chromosome structure around the ADAM33 locus and its interaction with other co-regulated genes which we will assess as biomarkers of ADAM33 activity; and b) dissect the function of ADAM33 in the context of smooth muscle and myofibroblast differentiation, contractility and ECM production. This will be related to expression in vivo, airway wall thickness (determined by endobronchial ultrasound), BHR, pre- and post-bronchodilator lung function.
(ii) Investigate the role of bone marrow-derived mesenchymal stem cells and circulating fibrocytes on BHR and remodelling with a specific focus on ADAM33 and its splice variants during their differentiation in the airways to fibroblasts, myofibroblast and smooth muscle cells.
(iii) Apply methodologies acquired from the studies in chronic adult asthma to samples obtained from children at the inception of the disease and during its progression.
Together, these translational studies will lead to a deeper understanding of the different sub-phenotypes of asthma, the mechanisms underlying disease chronicity in these groups and the role of ADAM33 in these processes; we also expect to identify biomarkers of early disease activity (including non-invasive markers in peripheral blood fibrocytes) that are predictive of disease chronicity and to identify novel targets for therapeutic intervention that are involved in pathways or processes that are insensitive to the effects of corticosteroids.

Publications

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An SS (2016) An inflammation-independent contraction mechanophenotype of airway smooth muscle in asthma. in The Journal of allergy and clinical immunology

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Bachert C (2012) Specific IgE against Staphylococcus aureus enterotoxins: an independent risk factor for asthma. in The Journal of allergy and clinical immunology

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Belvisi MG (2016) The ever-expanding ERS fellowship programmes: achievements over the past 3 years. in The European respiratory journal

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Bhimrao SK (2011) Airway inflammation in atopic patients: a comparison of the upper and lower airways. in Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

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Bousquet J (2014) Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop. in The Journal of allergy and clinical immunology

 
Description pamphlet 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Description of our ADAM33 research in the University's Post graduate pamphlet.

Increased interest in participating in respiratory research.
Year(s) Of Engagement Activity 2008,2016