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The role of the cross-talk between T cells and synovial fibroblasts in inflammatory osteoarthritis


   Institute of Inflammation and Ageing

  Dr S Jones, Prof Claudio Mauro  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Research interests/description of main research theme:

Background

Mesenchymal stromal fibroblasts have emerged as key mediators of the inflammatory response and drivers of localised inflammation. As such, they have been implicated in a number of chronic inflammatory conditions through modifying the microenvironment. A key driver of the phenotypic change of fibroblasts within inflammatory environments is now believed to be changes in the metabolic state of the cell. In normal physiological conditions, quiescent mesenchymal stromal fibroblasts exhibit a relatively high metabolic rate, compared to other cell types, maintaining substrate utilisation and ATP generation via glycolysis, pentose phosphate pathway and the tricarboxylic acid cycle (TCA). However, in inflammatory disease pathologies, there is now evidence that fibroblasts adopt an activated, highly metabolic phenotype, which is associated with disease progression by contributing to the inflammatory microenvironment through secretion of pro-inflammatory cytokines and structurally remodelling ECM to facilitate aberrant cellular invasion and growth.

Such metabolic changes happen in part through fibroblasts interactions with resident and circulating immune cells at inflammatory sites via various crosstalk mechanisms. The connection between metabolic changes, immune crosstalk and altered phenotype of fibroblasts in inflammatory microenvironments has clear implications for our understanding of how chronic inflammation is regulated and for the development of new anti-inflammatory therapeutics. Consistently, we have found that the metabolic profile of the synovial fibroblasts underpins their pro-inflammatory state. We hypothesise therefore that synovial joint inflammation is underpinned by metabolically-driven cross-talks between immune cells and fibroblasts that are therapeutically targetable. The overarching objective of this studentship is thus to pinpoint specific crosstalk mechanisms and target them for therapeutic purposes.

Environment

The project will be conducted within the Institute of Inflammation and Ageing, Queen Elizabeth Hospital, University of Birmingham. The Institute has state-of-the-art molecular and cellular biology laboratories together with strong collaborative links with NHS colleagues across several NHS Foundation Trust, including a partnership with the Royal Orthopaedic Hospital. We are therefore ideally positioned for access to clinical osteoarthritis patient samples and to the conduct all the techniques required for this translational project. This research environment will provide excellent training and development for anyone who wishes to pursue a research career in the area of ageing and inflammatory disease, with exposure to both clinicians and basic research scientists. The successful candidate will predominantly work under the supervision of Dr Simon Jones and Prof Claudio Mauro (University of Birmingham) and will receive training in a diverse range of techniques including Bioinformatics, primary cell culture, qRTPCR, and cellular metabolic assays. 

Person Specification

Applicants should have a strong background in biological sciences, and ideally a background in molecular and cellular biology. They should have a commitment to research in ageing and age-related inflammatory disease and hold or realistically expect to obtain the equivalent of at least an Upper Second Class Honours Degree in a relevant subject.

How to apply

Informal enquiries should be directed to Dr Simon W Jones (email ) or Prof Claudio Mauro ().

Applications should include the following

•             A detailed CV, including your nationality and country of birth;

•             Names and addresses of two referees;

•             A covering letter highlighting your research experience/capabilities;

•             Copies of your degree certificates with transcripts;

•             Evidence of your proficiency in the English language, if applicable.

 


Funding Notes

The project is for self-funding students and will be full-time for a period of 3 years

References

References
1. Philp AM, Davis ET, Jones SW. Developing anti-inflammatory therapeutics for patients with osteoarthritis. Rheumatology (Oxford). 2017 Jun 1;56(6):869-881.
2. Tonge DP, Pearson MJ, Jones SW. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics. Osteoarthritis Cartilage. 2014 May;22(5):609-21.
3. Pearson MJ, Herndler-Brandstetter D, Tariq M, Nicholson T, Philp AM, Davis ET, Jones SW*, Lord JM*. IL-6 secretion in osteoarthritis patients is mediated by chondrocyte-synovial fibroblast cross-talk and is enhanced by obesity. May 2017 Scientific Reports
4. Farah, H, Young, S, Mauro, C, Jones, S 2020, 'Metabolic dysfunction and inflammatory disease: The role of stromal fibroblasts', The FEBS journal. https://doi.org/10.1111/febs.15644
5. Pucino, V, Certo, M, Bulusu, V, Cucchi, D, Goldmann, K, Pontarini, E, Haas, R, Smith, J, Headland, SE, Blighe, K, Ruscica, M, Humby, F, Lewis, MJ, Kamphorst, JJ, Bombardieri, M, Pitzalis, C, Mauro, C 2019, 'Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring', Cell Metabolism, vol. 30, no. 6, pp. 1055-1074.e8.
6. Certo, M, Tsai, C-H, Pucino, V, Ho, P-C, Mauro, C 2020, 'Lactate modulation of immune responses in inflammatory versus tumour microenvironments', Nature Reviews Immunology. https://doi.org/10.1038/s41577-020-0406-2

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