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Trained innate immunity in atherosclerosis

  • Full or part time
  • Application Deadline
    Friday, January 10, 2020
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

This laboratory studies the role of the innate immune system (monocytes / macrophages) on the progression and regression of atherosclerosis. Recent work has shown how diabetes results in epigenetic changes in bone marrow progenitor cells that have important implications for atherosclerosis progression and, indeed, a range of common diseases.

Our fundamental approach is to interrogate human tissue (e.g. macrophages laser captured from atherosclerotic plaque or peripheral blood monocytes) using state of the art “-omics” approaches. We typically recreate and validate the findings in the relevant mouse model (with the aid of strong bioinformatics input) and then undertake intervention experiments in mouse (e.g. bone marrow transplant; gene editing) to test our hypothesis using a specific intervention in a validated system.

We intend to expand our programme of work on the metabolic drivers of epigenetic modification in bone marrow cells. We have recently implicated 3 transcription factors in the context of diabetes-induced trained immunity and have plans to further explore both the specific mechanisms and intervention that prevent and reverse these changes. The principal collaborators for this work are in New York (NYU); Boston (Broad Institute); Stockholm (Karolinska).


Training will be given in the relevant areas. We use a variety of techniques and technologies. Day to day: qRT-PCT; Western blotting; exosome extractions and analysis; laser capture microdissection; FACS; Seahorse metabolic analyses; immunofluorescence. We outsource RNA sequencing; ATAC seq and ChIP seq, but are actively involved in the interpretation of data by our bioinformatician. It is common in this laboratory to import specific techniques / collaborations to address a given experiment. All our students to date have been awarded their doctorate. Our students’ work is often recognised by prizes and awards and national and international meetings.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

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.

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.

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 build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

For October 2020 entry, the application deadline is 10th January 2020 at 12 noon (midday).

Please visit our website for more information on how to apply.

References

Akbar N, ….Choudhury RP.
Endothelium-derived extracellular vesicles promote splenic monocyte mobilization in myocardial infarction.
JCI Insight. 2017 Sep 7;2(17). pii: 93344. doi: 10.1172/jci.insight.93344.

Ruparelia N, Chai JT, Fisher EA, Choudhury RP.
Inflammatory processes in cardiovascular disease: a route to targeted therapies.
Nat Rev Cardiol. 2017 Mar;14(3):133-144. doi: 10.1038/nrcardio.2016.185. Review.

Ruparelia N, …Choudhury RP.
Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans.
Eur Heart J. 2015 Aug 1;36(29):1923-34. doi: 10.1093/eurheartj/ehv195. Epub 2015 May 16.

Cahill TJ, Choudhury RP, Riley PR.
Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics.
Nat Rev Drug Discov. 2017 Oct;16(10):699-717. doi: 10.1038/nrd.2017.106. Review.

Chai JT, Ruparelia N, Goel A, Kyriakou T, Biasiolli L, Edgar L, Handa A, Farrall M, Watkins H, Choudhury RP
Differential Gene Expression in Macrophages From Human Atherosclerotic Plaques Shows Convergence on Pathways Implicated by Genome-Wide Association Study Risk Variants.
Arterioscler Thromb Vasc Biol. 2018 Nov;38(11):2718-2730

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