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Modulation of macrophage phenotype and function in atherosclerosis by neutrophil microvesicles.


   Department of Infection, Immunity and Cardiovascular Disease

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  Dr V Ridger, Prof Endre Kiss-Toth  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Figures from the World Health Organisation show that cardiovascular disease is the leading cause of death globally. Atherosclerosis is the underlying cause of most of these deaths. It is a long-term inflammatory disease of the blood vessels that can lead to heart attack and stroke. White blood cells called monocytes accumulate in the vessel walls and become cells known as macrophages, which take up modified lipids and add to the inflammation. However, the most abundant white blood cell, the neutrophil, is rarely detected in the vessel wall. We found that neutrophils can release microvesicles - small, membrane-bound sacs that are a mini version of the cell – and that these stick to atheroprone regions of the vessel and accumulate there. We know microvesicles increase inflammation and atherosclerosis but don’t know what effect they have on macrophages. We think microvesicles can deliver their cargo to macrophages, changing their behaviour. We will look at how microvesicles change the content of macrophages and change the way macrophages work, including release of inflammatory molecules and the way they handle modified lipid. This project will advance our knowledge of the role of neutrophil microvesicles in atherosclerosis providing insight into new targets and novel ways in which to target the vessel wall.

This British Heart Foundation funded studentship will use cutting-edge research tools to investigate in more detail how neutrophil microvesicles affect the way macrophages behave and whether you can detect these changes in areas of blood vessels where atherosclerosis occurs to identify novel ways to reduce heart attacks and stroke caused by atherosclerosis. Initial experiments will involve co-culture of human macrophages with human neutrophil microvesicles. You will use miRNAseq and bioinformatics analysis to identify whether microvesicles alter the expression of miRs that regulate macrophage polarisation and function. Functional assays will then be used to verify that delivery of microvesicle miR does indeed alter macrophage function. Finally, you will use stored samples to carry out histological analysis using confocal microscopy to identify whether these changes occur in atherosclerotic plaques. This is a unique project that will provide training for you in multiple cutting-edge techniques and will add to the information we have already gathered regarding the role of neutrophil microvesicles in atherosclerosis that was published in Nature Communications.

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience.

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select Infection, Immunity and Cardiovascular Disease as the department.

Enquiries:

Interested candidates should in the first instance contact the primary supervisor Dr Victoria Ridger - [Email Address Removed]

Proposed start date: 1 March 2022


Funding Notes

This is a fully funded British Heart Foundation Non-clinical Studentship. BHF studentship stipend starting at £19,919 in year 1. Also included is a travel allowance of £1,000 to present research at or attend scientific meetings relevant to the project.

References

Selected references from the Ridger and Kiss-Toth groups:
1. Gomez I et al. Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium. Nat Commun. 2020; 11: 214.
2. Ajikumar A et al. Neutrophil-derived microvesicle induced dysfunction of brain microvascular endothelial cells in vitro. Int J Mol Sci. 2019; 20: 5227.
3. Johnston JM et al. Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion. Sci Adv. 2019; 5:eaax9183.
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