Treatment of rheumatoid arthritis (RA) has been transformed with the introduction of targeted therapies twenty years ago (comprising biologic disease modifying anti-rheumatic drugs, bDMARDS; and the more recent small molecule JAK inhibitors). Nevertheless, response to these agents is not universal, reflecting the heterogeneity of RA disease. A trial and error approach to drug selection, compounded by the absence of predictive biomarkers has led to cycling of ineffective therapies, and the (re-emergence) of refractory RA (RefRA) disease. Single-cell transcriptomics and mass cytometry methods have enabled the identification of an key immune cell popualtions and biological mediators of RA.
This project hypothesises that RefRA exhibits unique gene expression signatures and cellular subpopulation(s) with functional phenotypes. This may comprise a rare disease subgroup that has an intrinsically different biology from the outset +/- emerges with ongoing inflammation and exposure to therapy.
This project aims to establish the immune phenotype and gene signatures of RefRA towards target validation and novel treatment approaches.
The project will include recruitment of patients with RA that are well-phenotyped at the following stages: (i) early, active RA, targeted therapy naïve (ii) established, active RA refractory (inefficacy) to a minimum 2 different classes of bDMARD (iii) established RA refractory (inefficacy) to a minimum 2 different classes of bDMARD + a JAK inhibitor.
Peripheral blood and synovial tissue will be obtained from recruited patients. Single-cell technologies will be performed to investigate immune alterations, together with functional and intracellular signalling characterisation. Analysis of the multi-dimensional complex datasets will identify unique immune signatures that emerge with RefRA. These will be validated in an independent patient cohort using flow cytometry.
Training/techniques to be provided:
The student will be trained in clinical science, experimental design and immunology, and become expert in singl-cell techniques of blood and tissue. They will acquire an in-depth understanding of deep clinical phenotyping linked to the immunopathological processes of disease. Specific skills in laboratory and biostatistical and computing skills will provide invaluable interdisciplinary skills for future opportunities and career development.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject such as immunology, biological sciences, biomedical science. Candidates with experience in inflammatory diseases and interest in translational and experimental medicine are encouraged to apply.
How To Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.
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