Structure-function studies on protein coding region variants associated with asthma susceptibility

Asthma is a common disease with an unresolved aetiology affecting up to 10% of the population. Improving treatment options, particularly for severe refractory asthma requires a better understanding of disease mechanisms. Asthma is a complex disease involving both genetic and environmental factors (e.g. allergen exposure) resulting in disease expression. Molecular genetics holds great promise to identify new genes and pathways involved in asthma providing new therapeutic opportunities. Through linkage, candidate gene and genome-wide association studies a large number of genetic variants have been identified that are risk factors for the development of asthma. While a large proportion of these variants are thought to be regulatory and influence gene expression many variants also influence protein sequence and may therefore alter protein structure and function. For example, we have previously identified that genetic polymorphisms spanning the urokinase plasminogen receptor (uPAR) gene are associated with the risk of developing asthma. uPAR is a serine protease receptor that interacts with several ligands and has proteolytic (via plasmin activation) functions including extracellular matrix degradation as well as non-proteolytic functions, e.g. cell migration and proliferation.

This project aims to translate selected protein coding variants to insights into disease mechanisms using a combination of functional and structural approaches. The project will use recombinant protein expression and primary human airway cells to investigate functional effects of variants in e.g. receptors such as uPAR. These analyses will be complemented by structure determination of proteins carrying specific alleles using crystallography. Finally, the specific coding variants will be examined for association with clinical features of asthma using cohort based approaches.

Available to Home/EU/International students

Please email a CV with a covering letter to Professor Ian Sayers.