- 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.
Translating genetic findings to new understanding and therapeutic opportunities
There have been significant advances in the genetic epidemiology of lung function, but the causal genetic variants and causal genes, and the mechanisms by which they influence lung function, chronic obstructive pulmonary disease (COPD) and other respiratory diseases remain incompletely understood. Through a collaborative interdisciplinary endeavor involving a Universities of Nottingham, Leicester and Cambridge we will accelerate discovery of genetic risk factors for lung function impairment, and define the mechanisms and biological pathways underpinning the observed associations. This new Wellcome Trust Discovery Award will use new genomic data from population studies, building on the cross ancestry studies, and integrate with new multi-omic datasets using improved statistical genetic methodologies. To prioritise pathways we will undertake high-throughput functional genomic screens using CRISPR, perform lung digital spatial transcriptomic profiling and utilise informative cell and tissue models. This will inform in-depth mechanistic assays at the cell, tissue and organ scales to identify the key mechanisms underpinning regulation of lung function in health and disease.
Understanding virus - host interactions in the airways
Respiratory viruses such as rhinovirus and respiratory syncytial virus are known to contribute to exacerbation in respiratory diseases such as asthma. Current studies aim to further understand how these viruses interact with the host airway epithelium including developing new models and studying how genetics may be important in these interactions.
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of COVID-19, causes mild to severe respiratory illness exacerbated by aging and comorbidities. The virus has spread throughout the world leading to the current pandemic. Ongoing studies aim to understand the cellular and molecular mechanisms of how the virus interacts with the airway epithelium and leads to inflammation in the airways.
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. Ongoing studies 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. See recent publications examining IL33 and IL1RL1.
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 20 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 have now completed the largest moderate-severe asthma case-control analysis to date identifying new genetic loci. This study was a collaboration between; University of Nottingham, University of Leicester, U-BIOPRED 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 and other respiratory disease 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, see recent review. 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 Marios Georgiou, Dr Christopher Coleman, prof. Luisa Martinez-Pomares, Dr Rachel Clifford (Nottingham)
Prof. John Holloway (Southampton), Prof. Gerard Koppelman (Groningen), Prof. Liam Heaney (Belfast), Dr. Bianca Beghé (Modena), Prof. Angela Simpson (Manchester), Dr. Adel Mansur (Birmingham), Prof. Neil Thomson (Glasgow), Prof. Christopher Brightling, Prof. Martin Tobin, Dr. Louise Wain, Dr. Nick Shrine, Dr Katherine Fawcett, Dr Anna Guyatt (University of Leicester), Dr Emma Rawlins, Dr Joo-Hyeon Lee (Cambridge).
Michael Portelli, Kamini Rakkar, Philemon Gyasi-Antwi.
Current Postgraduate Research Students
Rebecca Cooper, Emma Szamek, Ashish Pradhan, Christina Shrees, Yousef Al Zahrani.
Previous Postgraduate Research Students
Guoqing Qian (PhD 2023), Yik Pang (PhD 2022), Karina Bingham (PhD 2022), Maria E. Ketelaar (University of Groningen, PhD 2021), Yousef Al Zahrani (MSc 2019), Binaya KC (PhD 2019), Robert Hall (PhD 2019), Amanda Lewis (MPhil 2018), Jonathan O'loghlin (MRes 2017), Sangita Bhaker (PhD 2017), Alexander Kheirallah (PhD 2017), Kelly Probert (MPhil 2016), Catherine Gowland (PhD 2015), Jon ewis (MRes 2014), Mariel Slater (PhD 2014), Michael Portelli (PhD 2013), Ma'en Obeidat (PhD 2012), Jane Fox (PhD 2011), Yize Wan (PhD 2011), Emily Hodge (PhD 2011), Asif Tulah (PhD 2010), Khalid Al Balushi (PhD 2009), Samantha Peel (PhD 2008).
The Wellcome Trust, Biotechnology & Biological Sciences Research Council, Asthma UK, National Institute of Health Research, Boehringer Ingelheim, GlaxoSmithKline plc, British Lung Foundation, Nottingham Hospitals Charity, British Medical Association, Medical Research Council, Hermes Fellowship.