Functional and –omics investigation of neutrophil activation in rheumatoid arthritis

Description

Neutrophils are key effector cells in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus and vasculitis. They contribute to disease progression via (i) production of reactive oxygen species (ROS) and proteases which damage host tissues (e.g. cartilage, vascular tissue); (ii) secretion of cytokines/chemokines which regulate the activity of both innate and adaptive immune systems; (iii) production of neutrophil extracellular traps (NETs), implicated in exposure of neo-epitopes (citrullinated proteins in RA, double-stranded DNA in SLE) to the immune system; (iv) exposure of auto-antigens (myeloperoxidase, proteinase-3) that cause generation of anti-neutrophil cytoplasmic antibodies (ANCA) in vasculitis. 

Neutrophils are activated in vitro by cytokines (e.g. TNF, GM-CSF, interferons) along with other immune mediators, such as immune complexes and toll-like receptor agonists. My research group has pioneered the application of RNA-sequencing to shed new insights into the regulation of neutrophil activation in RA, and in doing so have identified molecular signatures that indicate the presence of subsets of neutrophils called low-density granulocytes in certain RA patients, and a panel of genes that predicts response or non-response to TNF inhibitor therapy. We are now extending this global –omics approach to understanding neutrophil activation and response to drug therapy in RA through the application of 1H NMR metabolomics analysis of neutrophil intracellular metabolites; quantitative proteomics analysis of NETs; and computational modelling of RA transcriptomics datasets, clinical variables and therapy outcomes. 

One of the major challenges of treating patients with RA is the lack of clinical biomarkers that can predict whether a patient will respond to disease modifying anti-rheumatic drugs (DMARDs) or whether a particular patient will require treatment with a biologic therapy such as TNF-, IL-6- or JAK-inhibitors. Our overarching aim is to identify and validate neutrophil-derived molecular biomarkers for the development of a personalised medicine approach for the treatment of RA, and shed new insights into the complex role of neutrophils in the pathogenesis of RA. 

This studentship will extend our current analysis of transcriptomic data from RA patients, and integrate this with metabolomics analysis of RA neutrophils and biofluids. The broad aims of the project will be to: 

  1. Carry out analysis of existing RNA-seq datasets to identify gene expression profiles that correlate with clinical variables e.g. auto-antibody positivity, high levels of disease activity, responder/non-responder to therapy. In particular, transcriptome data already collected from RA patients pre- and post-DMARD therapy and from paired blood and synovial fluid neutrophils will be analysed. 
  2. Obtain new samples from RA patients to validate the predictions of the RNA-seq data (Aim 1). This validation will include subjecting peripheral blood and synovial fluid neutrophils to functional laboratory assays (apoptosis, chemotaxis, ROS production), analysing neutrophils by flow cytometry, and measuring gene and protein expression by qPCR and Western blotting. 
  3. Collect new samples of neutrophils, serum and urine from RA patients for metabolomics analysis. Samples will be collected from RA patients pre- and post- a range of therapies including DMARDs, TNF inhibitors and JAK inhibitors. 
  4. Computational analysis of multi-omic datasets along with relevant clinical variables. 

The student will also be provided with training in personal and professional development skills, by learning the following: planning their PhD, presenting research at seminars/conferences, creative thinking, problem solving and project management. 

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives. 

The successful candidate should have, or expect to have an Honours Degree at 2.1 or above (or equivalent). Candidates whose first language is not English should have an IELTS score of 6.5 or equivalent. This project is most suitable to a student with an undergraduate degree or Master’s degree in the Life Sciences (Biology, Genetics, Biochemistry, Biomedical Sciences, Cell Biology, and Medicine). 

To apply: please send your CV and a covering letter to hlwright@liverpool.ac.uk with a copy to iacdpgr@liverpool.ac.uk.

Availability

Open to students worldwide

Funding information

Self-funded project

The successful applicant will be expected to provide the funding for tuition fees, living expenses, attendance at conferences (around £1,500 per conference) and research costs of £10,000 per year. There is no funding attached to this project. Details of costs can be found on the University website.

Supervisors

References

  1. Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nature Reviews Rheumatology 2014; 10(10) 593-601. 
  2. Wright HL, Cox T, Moots RJ, Edwards SW. A novel set of biomarkers predicts response to therapy with tumour necrosis factor inhibitors in patients with rheumatoid arthritis. Journal of Leukocyte Biology 2017; 101 785-795 
  3. Wright HL, Makki F, Moots RJ, Edwards SW. Low density granulocytes: functionally distinct, immature neutrophils in rheumatoid arthritis with altered properties and defective TNF signalling. Journal of Leukocyte Biology 2017; 101 599-611 
  4. Wright HL, Thomas HB, Edwards SW, Moots RJ. Interferon gene expression signature in RA neutrophils correlates with a good response to TNFi therapy. Rheumatology 2015; 54(1) 188-193. 
  5. Wright HL, Thomas HB, Moots RJ, Edwards SW. RNA-Seq reveals activation of both common and cytokine-specific pathways following neutrophil priming. PLoS One 2013; 8(3) e58598. 
  6. Wright HL, Moots RJ, Bucknall RC, Edwards SW. Neutrophil function in inflammation and inflammatory disease. Rheumatology 2010; 49(9), 1618-31
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