Past Research
- The role of IgE in asthma and allergy.
- Pre-clinical drug development in asthma.
- The role of the uPA-uPAR axis in airway remodeling.
Future Research
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.
Getting stuck into mucus to find new treatments for severe asthma
The team of researchers led by Professor Ian Sayers have been awarded a £3M Medical Research Council (MRC) Programme Grant. The group is a collaboration of experts from the Universities of Nottingham, Leicester, Manchester, Leeds, Imperial College London and AstraZeneca.
The lungs produce the jelly-like substance mucus that acts as a gatekeeper controlling access of harmful agents, such as microbes and toxin, into the body by trapping and removing them via the action of airway epithelial cells. However, in asthma, a build-up of mucus with abnormal properties can plug the airways, making symptoms worse, which is known as an exacerbation.
The framework of mucus is provided by large molecules called mucins. In the lung there are two types of mucin (MUC5AC and MUC5B). This group of researchers, along with others, have already shown that MUC5AC is increased in airway mucus in asthma. Importantly, they have identified genetic changes near the genes encoding MUC5AC and MUC5B that alter the levels of these genes and affect the risk of severe asthma.
This programme of work aims to employ state-of-the-art techniques spanning biology and physics to understand the mechanisms that control how mucus is regulated in our airways, how it contributes to severe asthma and how we might target it for therapeutic benefit.
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 endeavour 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 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.
Advanced Interdisciplinary Models of dEstructive lung Disease: AIMED
Destructive lung diseases are the third largest cause of death worldwide, with chronic obstructive pulmonary disease (COPD) alone costing the NHS £1.9bn annually. COPD is characterised by destruction of the tissue that make up the air sacs (alveoli) within the lung, leading to airspace enlargement, which reduces the ability of the lung to exchange carbon dioxide and oxygen (i.e. loss of lung function). Lung tissue destruction in COPD is complex, with multiple mechanisms causing lung tissue damage. In contrast, lymphangioleiomyomatosis (LAM), another lung disease associated with tissue destruction that can cause respiratory failure and death, involves a single gene and has a well-understood progression. LAM is rare, primarily affecting younger females; however, the simpler nature of LAM allows a more straightforward starting point for interdisciplinary study of lung tissue destruction and makes it an effective model system for understanding destructive lung disease more widely. We will exploit this to develop and validate mathematical, imaging, and biological approaches for subsequent application to COPD and with broader implications for destructive lung diseases.
This UKRI Cross Research Council Responsive Mode grant brings together significant expertise and includes researchers at Universities of Nottingham, Leicester, Birmingham and the Diamond Light Source.
Getting the right drug to the right patient
As part of the Nottingham NIHR Biomedical Research Centre we have several programmes of work using different -omics platforms to identify patients most likely to gain benefit from biological drugs in severe asthma. Recently we have shown that a nasal gene signature at 3 months can identify patients that went on to have a clinically relevant response to mepolizumab at one year. See paper in AJRCCM. Ongoing studies aim to understand the mechanisms of mepolizumab action in the airways and potentially identify blood-based biomarkers.
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 Prof 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.
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.
Collaborators
Prof. Ian Hall, Dr Marios Georgiou, Dr Christopher Coleman, Prof. Luisa Martinez-Pomares, Dr Rachel Clifford, Prof. Bindi Brook, Prof. Simon Johnson, Prof. Reuben O'Dea (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, Dr. Dominick Shaw, dr. Himanchu Kaul (University of Leicester), Dr Emma Rawlins, Dr Joo-Hyeon Lee (Cambridge), Prof. Gowsihan Poologasundarampillia (University of Birmingham), Prof. Ian Adcock (Imperial), Prof. David Thornton (University of Manchester), Prof. Gleb Yakubov (University of Leeds), Dr. Luke Bonser (AstraZeneca).
Research Staff
Robert Hall, Alex Clay, Bridget Evans, Suzannah Entwistle, Rohan Paranjpe, Bitasadat Hosseini, Mobina Khadivar.
Current Postgraduate Research Students
Yousef Al Zahrani, James Eastall, Matthew Saward, Holly Pedley, Eryk Gadomski, Man Yin Melanie, Angus Spence
Previous Postgraduate Research Students
Emma Szamek (PhD, 2025), Rebecca Cooper (PhD, 2025), Ash Pradhan (PhD, 2024), 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).
Funding
The Wellcome Trust, UKRI, Medical Research Council, 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.