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Anti-inflammatory effects of glucocorticoids on immune cell metabolism


Institute of Inflammation and Ageing

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Prof A Clark , Dr Sally Clayton , Dr M Kurowska-Stolarska No more applications being accepted Funded PhD Project (UK Students Only)
Birmingham United Kingdom Bioinformatics Cell Biology Immunology Molecular Biology

About the Project

Research interests/description of main research theme:

Glucocorticoids (GCs) inhibit pro-inflammatory functions of many immune cells that contribute to chronic immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) [1]. For more than seventy years they have been extensively used to treat RA and many other inflammatory diseases. In fact many RA patients remain dependent on GCs for long term management of their symptoms, despite the fact that GCs can cause numerous harmful side effects via disruption of metabolic equilibrium [2]. This PhD project will explore a novel mechanism that contributes to the anti-inflammatory actions of GCs, with the aim to discover whether beneficial and harmful effects of these important and perplexing compounds can be separated.

The relatively new field of Immunometabolism is based on the concept that immune cells must adapt their metabolic activities in order to mount effective responses to challenge [3]. Metabolic adaptations include changes in mitochondrial functions and in the utilisation of glucose and other fuels. We have found that GCs oppose metabolic adaptations that underpin the inflammatory responses of macrophages and other immune cells. We do not yet understand the molecular mechanisms responsible for this effect; the full extent of the consequences for immune cells; or the extent to which similar changes happen in patients whose inflammatory conditions are treated with GCs.

The student will use a variety of state-of-the-art molecular biological and biochemical methods to investigate metabolic and inflammatory activities of macrophages and other immune cells. They will also use cutting edge single cell RNA sequencing methods to investigate changes of gene expression in the joint tissues of rheumatoid arthritis patients following treatment with GCs. These methods are fully established in the labs of the two principal supervisors, Andy Clark (Birmingham) and Mariola Kurowska-Stolarska (Glasgow) [4]. Finally, the student will have the opportunity to develop skills in Patient and Public Involvement (PPI), which are critical for anyone wishing to undertake a career in biomedical research. It is expected that the outputs of this research will shed light on the balance between harmful and beneficial actions of GCs, and result in at least one high impact publication.

This is a four year PhD studentship funded by Versus Arthritis via RACE2 (Research into Inflammatory Arthritis Centre Versus Arthritis), a Centre of Excellence that brings together researchers from the Universities of Birmingham, Glasgow, Newcastle and Oxford.

Person Specification

Applicants should have a strong background in Biological Sciences, and ideally a background in Immunology or Bio-informatics. They should have a commitment to research in inflammatory disease and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject. 

How to apply

Informal enquiries should be directed to Prof. Andy Clark ([Email Address Removed])

To apply, please send: 

• 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

Support includes an annual stipend at RCUK rates for 4 years, PhD registration fees at UK student rate, research expenses and travel costs.

References

References
1. Cain, D. W., and J. A. Cidlowski. 2017. Immune regulation by glucocorticoids. Nat Rev Immunol 17: 233-247.
2. Buttgereit, F. 2020. Views on glucocorticoid therapy in rheumatology: the age of convergence. Nat Rev Rheumatol 16: 239-246.
3. O'Neill, L. A., R. J. Kishton, and J. Rathmell. 2016. A guide to immunometabolism for immunologists. Nat Rev Immunol 16: 553-565
4. Alivernini, S., MacDonald, L., Elmesmari, A., Finlay, S., Tolusso, B., Gigante M.R. et al. 2020. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med 26: 1295-1306
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