(MRC DTP) Understanding mechanisms in connective tissue disease through MALDI Mass Spectrometry analysis

Only two drugs have been licensed for any connective tissue disease (CTD) in the past 50 years. CTDs still therefore carry a significant burden of mortality and morbidity. There is an urgent need to improve our understanding of disease mechanisms in CTD in order to provide for a better taxonomy of this phenotypic grouping. This will allow us to identify patient subsets based on shared immunopathogenesis, and allow for early detection of co-morbidities. Such efforts are essential to aid diagnosis, management and ultimately facilitate more targeted therapies and thus personalised management approaches.

We have currently recruited 300 patients to our BRC funded Lupus Extended Autoimmune Phenotype (LEAP) cohort study; these adult patients have CTD and disorders including Systemic Lupus Erythematosus and Scleroderma. We have undertaken genomic and targeted transcriptomic approaches to identify subsets with a common immunopathogenesis. We have for example shown that approximately 30% of the cohort have a high level of the pro-inflammatory cytokine Type I Interferon signature, which is of particular interest as this enhances our understanding of the disease mechanism (An et al, 2016) and means that a sub-set of the cohort likely have key clinical features which may respond to targeted experimental therapies, such as interferon blockade (Furie et al, 2017).

Type I interferon has long been associated with Systemic Lupus Erythematosus and Scleroderma, however what is needed to enhance disease understanding in this area forward is an unbiased proteomic approach to identify novel markers of CTD. These diseases have significant clinical overlap but also differences and we predict that lipid, protein and other profiles will also allow differentiation. Thus we aim, using MALDI mass spectrometry, to identify overlapping and distinct markers, which can be used to assist in disease understanding, and ultimately guide future treatment choice and monitoring.

This project will be undertaken in collaboration with our industrial partner ASTA (Applied Surface Technology Ascend). ASTA UK Ltd focuses on the development, manufacturing and promotion of state-of-the-art diagnostics platforms based on MALDI mass spectrometry. The student will therefore gain invaluable industry experience, as well as training in the academic setting.

Prof Ian Bruce: https://www.research.manchester.ac.uk/portal/ian.bruce.html
Dr Tracy A Briggs” https://www.research.manchester.ac.uk/portal/Tracy.Briggs.html
ASTA: astams.com