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Iron is required for fundamental processes in cellular physiology including mitochondrial electron transport, nucleotide biosynthesis, and epigenetic regulation. Immune cells acquire iron from plasma via the transferrin receptor. Rapid proliferation and dynamic changes in gene expression and metabolism are central to the adaptive immune response; furthermore, distinct T cell subsets differ in their immunometabolic phenotypes (Phan et al, Immunity 2017).

A recent study identified a severe combined immunodeficiency phenotype caused by a mutation in the transferrin receptor gene that caused significantly impaired cellular iron acquisition (Jabara et al, Nat Genet 2016). This defect markedly inhibited T/B cell proliferation and antibody class-switching, explaining the immunodeficiency. These data revealed the concept that adaptive immunity is highly compromised, leading to fatality in some cases, when immune cells are unable to access iron. The mutation in transferrin receptor is extremely rare and is currently known in only two families. However, iron deficiency, which also decreases iron availability to cells, is extremely common, affecting around a billion people worldwide and is particularly prevalent in children and pregnant women (Global Burden of Disease Study, The Lancet 2017). This project will investigate how iron deficiency alters the function of the immune system. We have developed a range of reagents and protocols to specifically manipulate serum iron concentrations by altering expression of the iron regulatory hormone, hepcidin (Drakesmith and Prentice, Science 2012; Armitage et al, J Innate Immun 2016). We will match these ‘iron tools’ with a panel of immunological techniques including vaccination strategies, mass cytometry and flow cytometry, single-cell RNA-Seq, advanced microscopy and metabolomics to investigate how iron deficiency influences the function of dendritic cells, iron trafficking within the lymph node, and generation of immunological responses and memory. We are interested in manipulating iron availability to regulate the immunity in the context of infection, immunotherapy of cancer and autoimmune disorders.

Training Opportunities

The project is based at Weatherall Institute of Molecular Medicine, which is a multi-disciplinary institute, providing wide-ranging opportunities for research training. This project specifically entails mass and flow cytometry, gene expression analysis using a variety of platforms, advanced microscopy and metabolomics, and use of transgenic animals, although many more methods are also likely to be employed. We collaborate with other groups overseas and there will be opportunity to travel to these labs and work there. Students will also attend international conferences and present data.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1 Phan AT, Goldrath AW, Glass CK. Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity. Immunity. 2017 May 16;46(5):714-729 - https://www.ncbi.nlm.nih.gov/pubmed/28514673
2 Jabara HH, Boyden SE, Chou J, Ramesh N, Massaad MJ, Benson H, Bainter W, Fraulino D, Rahimov F, Sieff C, Liu ZJ, Alshemmari SH, Al-Ramadi BK, Al-Dhekri H, Arnaout R, Abu-Shukair M, Vatsayan A, Silver E, Ahuja S, Davies EG, Sola-Visner M, Ohsumi TK, Andrews NC, Notarangelo LD, Fleming MD, Al-Herz W, Kunkel LM, Geha RS. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet. 2016 Jan;48(1):74-8 - https://www.ncbi.nlm.nih.gov/pubmed/26642240
3 GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017 Sep 16;390(10100):1211-1259 - https://www.ncbi.nlm.nih.gov/pubmed/28919117
4 Drakesmith H, Prentice AM. 2012. Hepcidin and the iron-infection axis.Science,  338 (6108), pp. 768-72. - http://www.ncbi.nlm.nih.gov/pubmed/23139325
5 Armitage AE, Lim PJ, Frost JN, Pasricha SR, Soilleux EJ, Evans E, Morovat A, Santos A, Diaz R, Biggs D, Davies B, Gileadi U, Robbins PA, Lakhal-Littleton S, Drakesmith H. Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia. J Innate Immun. 2016;8(5):517-28 - https://www.ncbi.nlm.nih.gov/pubmed/27423740

Research Themes, Tools and Technologies

Supervisors

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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