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Invariant Natural Killer T-cells in atherogenesis

Objective

Many survivors of childhood chronic disease struggle with early atherosclerosis later in life. As a physician-scientist I am inspired by their lifelong fight, and my research focuses on the etiology and treatment of early atherosclerosis. Here, I aim to unravel the role of invariant Natural Killer T-cells (iNKTs) in atherogenesis. iNKTs are unique for their restriction to lipid antigens presented on CD1d molecules, which underlies their pivotal role in lipid-driven disorders such as atherosclerosis. The exact role of iNKTs however remains elusive, as long as the involved plaque-associated lipid antigens have not been identified. Therefore, I developed CD1d-sortagging as a novel and innovative approach for lipid antigen identification. CD1d-sortagging employs bacterial sortase enzymes for site-specific cleavage and biotin labeling of CD1d-lipid antigen complexes, followed by isolation and mass spectrometry identification of the lipid antigens. At the Cardiovascular Immunology laboratory of Prof. Monaco at the Kennedy Institute of Oxford University, in a unique collaboration with renowned iNKT-glycolipid expert Prof. Cerundolo, I first aim to identify plaque-associated lipid antigens. CD1d-sortagging will be applied ex vivo in a human atheroma model, and in vivo in a CD1d1-sortagging mouse model for atherosclerosis. Upon identification, I secondly aim to unravel the impact of plaque-associated lipid antigens on iNKT cell phenotype and function using Mass Cytometry of plaque-resident immune cells and study the structural and functional aspects of plaque lipid-iNKT cell interaction. Finally, I will explore the therapeutic potential of plaque-associated lipid antigens to manipulate iNKT cell function and atherogenesis in a mouse model for atherosclerosis. Taken together, this proposal combines an innovative approach and excellent research setting with translational impact, an effective work plan, and maturation of a passionate physician-scientist.

Fields of science (EuroSciVoc)

Programme(s)

Topic(s)

Funding Scheme

MSCA-IF-EF-ST - Standard EF

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Call for proposal

(opens in new window) H2020-MSCA-IF-2017

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Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Net EU contribution
€ 195 454,80
Address
WELLINGTON SQUARE UNIVERSITY OFFICES
OX1 2JD Oxford
United Kingdom
Region
South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 195 454,80