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PhD in Systems Immunity: Understanding disease heterogeneity in inflammatory arthritis

This funding opportunity has expired.

Key facts

Application deadline 5 August 2019
Start date 1 October 2019
Duration 3 years, with part of 2nd year based in Monash University, Australia
Level of study Postgraduate research
Award type PhD studentship
Number of studentships 1

Does the adaptation of Jak-STAT signalling by protein tyrosine phosphatases affect the heterogeneity of synovitis seen in inflammatory arthritis?

Joint biopsies from patients with rheumatoid arthritis show that the histological features of joint inflammation (synovitis) are highly heterogeneous and vary between patients. As a result, patients with rheumatoid arthritis often display an inadequate response to existing biological drugs. To improve patient stratification, and clinical decisions on the best course of therapy studies will identify the pathways responsible for determining the heterogeneity of synovitis in rheumatoid arthritis.

Background

Biological drugs (e.g., tocilizumab) or oral inhibitors (e.g., tofacitinib) used in the treatment of rheumatoid arthritis often target cytokine signalling via the Janus-activated kinase (Jak)-Signal Transducer and Activator of Transcription (STAT) pathway. These cytokines contribute to the onset and maintenance of autoimmunity and the development of synovitis. By comparing Jak-STAT signalling in response to IL-6 and IL-27 we have identified that activities associated with the transcription factors STAT1 and STAT3 affect the histological features of synovitis. It is therefore proposed that changes in the control of STAT1 or STAT3 may affect the heterogeneity of joint disease.

Jak-STAT signalling is controlled at multiple levels, but includes a regulatory interplay between individual STAT transcription factors – termed cross-regulation. For example, STAT1 and STAT3 often counteract each other to affect the transactivation of genes involved in survival, proliferation and functional identity. By tracking cytokine responses in the inflamed synovium (in mouse models and human synovial biopsies) and CD4+ T-cells we have identified the protein tyrosine phosphatases PTPN2 and PTPN22 as important regulators of Jak-STAT signalling. Using next generation sequencing technologies (e.g., ATAC-seq, ChIP-seq, RNA-seq) studies will determine how PTPN2 and PTPN22 shape the transcriptional output of Jak-STAT signalling to influence the course of synovitis.

You will join a collaborative team sharing interests in cytokine receptor signalling, protein tyrosine phosphatases, and the role of T-cells in autoimmune disease. Further details of the research area are available in the following publications:

  • Twohig, JP., Cardus Figueras, A., et al., Activation of na├»ve CD4+ T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4+ T cells. Nature Immunology 20 (4):458-470 (2019)
  • Jones, G.W., et al., Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. Journal of Experimental Medicine 212 (11): 1793-180

This PhD studentship spans 3 years, with part of 2nd year based in Monash University, Australia.

Supervisors

Professor Tony Tiganis and Professor Stephen Turner from Monash University, Australia, will also be involved in the research.

The collaborative team share common interests in cytokine receptor signalling, protein tyrosine phosphatases, and the role of T-cells in autoimmune disease. Early interactions between the Supervisors have led to several prominent publications (e.g., Nature Immunology, 2019; Diabetes, 2019; Cell Reports, 2018), and the exchange of post-doctoral fellows (e.g., Sir Stanley Thomas Systems Immunity Travel Fund Scheme, UUKI Rutherford Scheme) between Cardiff and Monash.

Thus, you will enter a vibrant and productive research team with the ambition to build on these initial successes. Each Supervisor will provide individual expertise essential to the delivery of the research – these include access to next generation sequencing methods and existing datasets, genetically modified mice, animal models of disease and methods to evaluate immune and inflammatory responses.

All necessary support is available to mentor and support you. The research will be conducted jointly between Cardiff University and Monash University, and you will spend you second year of studies in Australia before returning to Cardiff to complete your studies.

Funding details

Tuition fee support Full UK/EU tuition fees
Maintenance stipend Doctoral stipend matching UK Research Council National Minimum
Additional funding offered The project benefits from project and programme grant funding already supporting next generation sequencing methods and investigations in animal models of inflammatory arthritis.

Eligibility criteria

Residency Open to all UK/EU students without further restrictions
Academic criteria

Minimum degree classification – B.Sc. Hons 2.1 (or equivalent) in a biological related degree subject

A Master’s degree in a relevant subject area (e.g., Immunology, molecular cell biology, bioinformatics and genetics) will be favourably considered.

Any prior laboratory experience should be highlighted with the application.

The student will be supported to ensure all appropriate documentations for working in Australia as a PhD student are in place.

Consideration is automatic upon application for admission to the Doctor of Philosophy in Medicine with an October 2019 start date.

Please provide a statement to identify your willingness to work in Australia for an extended period of time, and explain how this opportunity will enhance your career aspirations.

In the "Research proposal and Funding" section of your online application, please specify the project title and supervisors of this project and copy the project description in the text box provided.

Please select “No, I am not self-funding my research” when asked whether you are self-funding your research.

Please add ‘PhD in Systems Immunity: Understanding disease heterogeneity in inflammatory arthritis’ when asked "Please provide the name of the funding you are applying for".

We reserve the right to close applications early should sufficient applications be received.

Eligible research programmes