- The role of IgE in asthma and allergy.
- Pre-clinical drug development in asthma.
Estimates suggest that 100-150 million people worldwide have asthma. In the UK the prevalence of asthma is particularly high, a recent report showed that in Scotland more than 18% of people experienced asthma symptoms and in England and Wales similar figures were reported, 17% and 15.3% respectively (Global Initiative for Asthma 2004). COPD is a composite term encompassing several diseases including chronic bronchitis and emphysema. COPD is the fourth most common cause of death worldwide (WHO 2004). Asthma and COPD are complex diseases involving both genetic and environmental factors resulting in disease expression.
Functional genomics of the IL33/ST2 axis: a therapeutic target in asthma
The interleukin 33/suppression of tumorigenicity 2 (IL33/ST2) axis has been implicated in multiple human diseases including asthma. ST2 being the receptor for IL33. In particular we and other have shown that genetic polymorphisms spanning the IL33 and IL1RL1 (gene encoding ST2) have been reproducibly associated with asthma diagnosis. ST2 can exist in multiple forms including a membrane form that signals when IL33 is bound and a soluble form thought to act as a decoy receptor. However, the causative nature of the genetic changes spanning the IL33 and IL1RL1 gene loci are unclear at this time. Interestingly, the IL33/ST2 axis may be particularly important in airway epithelial function in asthma. In a new major grant from Asthma UK we aim to further define the genetic association between variants in IL33 and ST2 genes with clinical features in asthma and importantly using tissue and primary cells from asthma patients further define the functional effects of gene polymorphism. This study brings together scientists from six centres for respiratory research across the UK, see press release.
Genetics of Asthma Severity & Phenotypes (GASP) Initiative
As part of an ongoing Asthma UK study Dr Sayers's group have developed a new cohort, the Genetics of Asthma Severity and Phenotypes (GASP) initiative that aims to generate a very large group of asthma patients with extensive clinical information for genetic studies. Recruitment is ongoing involving 16 centres across the UK. The ultimate aim is to have genome wide association data for all subjects allowing genetic association testing for asthma and clinical features of asthma. We are actively looking for new centres to collaborate.
As part of GASP we have also identified asthma patients with moderate-severe asthma and plan to conduct one of the largest severe asthma case-control analysis to date using genetic data from UK Biobank, this study is a collaboration between; University of Nottingham, University of Leicester and AirPROM.
Airway remodeling genetics
We have identified the Urokinase Plasminogen Activator Receptor (UPAR/PLAUR) gene as an asthma susceptibility gene . uPAR plays a key role in the formation of the serine protease plasmin by interacting with urokinase plasminogen activator (uPA) and has been implicated in many processes including orchestrating structural changes in the airways of asthma patients called airway remodeling. We have identified that uPAR expression is elevated in the airways and blood of asthma patients and may identify a more severe, non atopic disease. Airway remodeling is characterized by; smooth muscle hypertrophy/hyperplasia, sub-epithelial fibrosis, basement membrane thickening, increased extracellular matrix (ECM) deposition and more recently epithelial metaplasia and goblet cell hyperplasia have been identified. Airway remodeling leads to accelerated decline in lung function in asthma, and is not adequately targeted by existing asthma drugs. We have identified that uPAR is elevated in the bronchial epithelium in asthma and contributes to wound/repair responses providing evidence for a role in airway structural changes.Ongoing studies aim to determine the mechanistic basis of this association and explore the potential of targeting uPAR in asthma for clinical benefit.
Lung function genetics
Forced Expiratory Volume in 1 second (FEV1) and FEV1/Forced Vital capacity (FVC) ratio are important predictors of population morbidity and mortality and form the basis of the diagnosis of COPD. Hereditability estimates for FEV1 are as high as 0.77. Using Genome Wide Association (GWA) approaches in 20,288 individuals of European decent (Phase 1) and ≥32,184 additional individuals (Phase 2) we identified association with common variants in TNS1, GSTCD and HTR4 for FEV1 and HHIP, AGER and THSD4 for FEV1/FVC (see manuscript). Ongoing studies aim to determine the functional significance of these associated polymorphism and their contribution to COPD. To date, we have investigated HTR4, AGER, GSTCD and INTS12 for their role in these mechanisms and during lung development.
Targeting the airway epithelium in asthma
The airway epithelium represents a critical interface between the environment and the tissue of the airways. Under normal conditions the epithelium is composed of ciliated columnar, mucus secreting goblet and Clara cells that secrete surfactant. In asthma, epithelial desquamation and dysfunction including impaired barrier function and repair capacity have been reported. Epithelial damage and abnormal repair shows a correlation with the development of bronchial hyper-responsiveness (BHR) in asthma subjects. Ongoing studies aim to further our understanding of molecular mechanisms underlying these alterations in airway epithelial function using ex vivo models and may provide therapeutic opportunities for asthma. Similarly, we are developing new sampling techniques to obtain primary airway epithelial cells from the airways of asthma and control subjects to further study disease specific mechanisms (in collaboration with Dr Dominick Shaw).
Prof. Ian Hall, Dr. Dominick Shaw, Dr Cynthia Bosquillon (Nottingham)
Prof. Christopher Brightling (Leicester), Prof. John Holloway (Southampton), Prof. Gerard Koppelman (Groningen), Dr. Bianca Beghé (Modena), Prof. Angela Simpson (Manchester), Dr. Adel Mansur (Birmingham), Prof. Neil Thomson (Glasgow), Dr. Charlotte Dean (Imperial), Professor Martin Tobin, Dr. Louise Wain, Dr. Nick Shrine, Dr. Maria Soler Artigas (University of Leicester).
Current PhD Students
Jonathan O'Loughlin, Jon Lewis, Amanda Lewis, Robert Hall, Binaya KC
Previous PhD Students
Alexander Kheirallah (Awarded 2017), Catherine Gowland (Awarded 2015), Mariel Slater (Awarded 2014) Michael Portelli (Awarded 2013) Ma'en Obeidat (Awarded 2012) Jane Fox (Awarded 2011) Yize Wan (Awarded 2011) Emily Hodge (Awarded 2011) Asif Tulah (Awarded 2010) Khalid Al Balushi (Awarded 2009) Samantha Peel (Awarded 2008)
Asthma UK, British Lung Foundation, Nottingham Hospitals Charity, Biotechnology & Biological Sciences Research Council, British Medical Association, Medical Research Council, Hermes Fellowship.