Dr Ian Sayers
Telephone: +44 (0)115 82 31066
Email: ian.sayers@nottingham.ac.uk
Personal Profile
Ian Sayers graduated with a B.Sc. in Biochemistry from Sheffield University, UK in 1993. He stayed at Sheffield and undertook research into the molecular basis of Immunoglobulin E (IgE) receptor interactions with a focus on therapeutic intervention in allergy graduating with a Ph.D in 1997. Dr Sayers has maintained his research interest in the molecular basis of asthma and allergy spending time with the Asthma Genetics Group in Southampton, UK (1998-2001) and in pre-clinical drug development in New Zealand at the Genesis Research and Development Corporation and the Malaghan Institute (2001-2003). In 2004, Dr Sayers joined the Division of Therapeutics & Molecular Medicine in Nottingham.
Research Interests
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.
Urokinase Plasminogen Activator Receptor
In collaboration with The University of Southampton and The University of Groningen, we have identified the Urokinase Plasminogen Activator Receptor (UPAR/PLAUR) gene as an asthma susceptibility gene and a determinant of lung function decline in asthma. uPAR is expressed in multiple isoforms and 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 airway remodelling (see manuscript and Figure). Airway remodelling is characterised 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 remodelling leads to accelerated decline in lung function in asthma, and is not adequately targetted by existing asthma drugs.
We have recently identified that uPAR expression is elevated in the bronchial epithelium of asthma patients and that elevated uPAR leads to defective epithelial repair (see manuscript). Ongoing studies aim to clarify the role of uPAR in airway remodelling in asthma.
Airway Epithelium
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 BHR in asthma subjects. Ongonig studies aim to develop models to further our understanding of molecular mechanisms underlying these alterations in airway epithelium function. 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 Dominck Shaw).
Genetic Determinants of Lung Function
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 alleles and the contribution of polymorphisms to COPD.
Leukotriene Genetics
Leukotrienes are lipid mediators released by inflammatory cells (white blood cells) that migrate from the blood into the lungs of people who have asthma or COPD. Leukotrienes act on lung cells (via receptors) to cause airway narrowing (bronchoconstriction), swelling of the airway wall (oedema), and blockage of the airway with mucus. Our work aims to identify very small changes (polymorphisms) in the genes that encode for the enzymes and receptors that are involved in the production and activity of leukotrienes and in particular see if combinations of polymorphisms in different genes predispose people to develop asthma or COPD or a more severe form of these diseases.
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