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The role of neutrophil microvesicles in regulation of endothelial cell inflammation


   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

Supervisor(s): Dr Victoria Ridger, Professor Endre Kiss-Toth and Professor Kong Peng Lam

Figures from the World Health Organisation show that cardiovascular disease (CVD) is the leading cause of death globally. Atherosclerosis is the underlying cause of most of these deaths. It is a long-term disease of the blood vessels, where fat and inflammation builds up in the walls of arteries that can lead to heart attack and stroke. Neutrophils, the most abundant white blood cell-type in the circulation, drive atherosclerosis via mechanisms that remain incompletely understood. Neutrophils produce microvesicles, small bags of biological material, and higher levels of these microvesicles have been found in patients with heart disease. We demonstrated that neutrophil microvesicles like to stick to parts of arteries where atherosclerosis happens, and that they can increase the inflammation and fat build-up in these areas.

This A* studentship will use cutting-edge research tools to investigate in more detail how neutrophil microvesicles affect the way cells that line arteries behave in areas of blood vessels where atherosclerosis occurs and aim to identify novel ways to reduce heart attacks and stroke, caused by atherosclerosis. Initial experiments will involve culture of human coronary artery endothelial cells under flow conditions using an Ibidi pump system in the Ridger lab in Sheffield. Microvesicles will be prepared in the lab by primary cell isolation, quantified using a Cytek Aurora and then added to the endothelial cells. These samples will then be used to carry out the analysis in Professor Lam’s group in Singapore using CyTOF, Luminex and miRNAseq and single cell RNAseq. 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.

Selected references from the Ridger, Kiss-Toth and Lam groups:

1. Gomez I, Ward B, Souilhol C, Recarti C, Ariaans M, Johnston J, Burnett A, Mahmoud M, Luong LA, West L, Long M, Parry S, Woods R, Hulston C, Benedikter B, Bazaz R, Francis S, Kiss Toth E, van Zandvoort M, Schober A, Hellewell P, Evans PC, Ridger V. Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium. Nat Commun. 2020; 11: 214.

2. Johnston JM, Angyal A, Bauer RC, Hamby S, Suvarna SK, Baidžajevas K, Hegedus Z, Dear TN, Turner M; Cardiogenics Consortium, Wilson HL, Goodall AH, Rader DJ, Shoulders CC, Francis SE, Kiss-Toth E. Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion. Sci Adv. 2019; 5:eaax9183.

3. Loh JT, Xu S, Huo JX, Kim SS, Wang Y, Lam KP. Dok3-protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunity. J Clin Invest. 2019; 129: 2717.

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience. This project involves travelling to the partner institute in Singapore so applicants must be prepared to spend up to 2 years abroad.

How to apply:

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/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 Dr Victoria Ridger ([Email Address Removed])

Funding: 

Proposed start date: 1/10/2022

Salary/stipend rate: For each student admitted to the 4-year programme, A*Star will provide the following financial support, whilst the student is in Singapore:

• Living allowance: A monthly stipend of two thousand, seven hundred Singapore Dollars (~£1,475) whilst in Singapore.

• A one-off "settling-in allowance" of one thousand Singapore dollars (~£530).

• A one-time airfare allowance of one thousand five hundred Singapore dollars (~£800).

• One-time IT allowance of eight hundred Singapore dollars (~£425)

• Consumables and Bench Fees incurred by students when based at A*Star in Singapore.

• Cost of medical insurance while the student is based at A*Star.

• Medical insurance, Housing subsidy, Conference allowance while the student is based at A*Star.

Whilst in Sheffield, students receive fees and stipend (at the RCUK rate, £4,500 & £15,609 in 2021/22).

In addition, students will be able to claim up to £500 from Sheffield towards the costs of an airfare back to the UK whilst they are in Singapore in order to make a home visit. This will normally be available for students who meet the normal expectations of spending approximately half of the programme in Singapore. This allowance is not available for those NOT spending 50% of the programme time in Singapore


Funding Notes

Funding:
Fully funded by the A*Star-University of Sheffield Research Attachment PhD Programme. See below for further information.
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