Kennedy Trust Prize Studentships
A novel arterial macrophage subset in atherosclerosis
Obesity, insulin resistance, type 2 diabetes (T2D), and associated cardiovascular disease (CVD) often coexist clinically and constitute an epidemic global health problem. Metabolic diseases are associated with inflammation of metabolic and endocrine tissues. The molecular underpinnings of metabolic inflammation are ill defined but myeloid cells are believed to be central to the development of metabolic diseases (1). We have recently demonstrated that myeloid deficiency in Interferon Regulatory Factor (IRF)-5 protects from the pre-diabetic state of insulin resistance in diet-induced obesity (2). We have also developed models of atherosclerosis (3) and observed that IRF5 deficiency reduces size of atherosclerotic lesions and selectively ablates a CD11c+ macrophage subset in the aorta, suggesting that IRF5 supports the maintenance of pro-inflammatory CD11c+ macrophages in metabolic disease. This project aims to investigate the biology and molecular regulation of CD11c+ macrophages and how they function in atherosclerosis. The results will contribute to our understanding of the increased risk of atherosclerosis in patients with metabolic diseases and it will explore the fundamental molecular mechanisms regulating macrophage programming in metabolic inflammation.
The project will provide training in models of atherosclerosis and in state-of-the-art single cell platforms (e.g. mass cytometry (CyTOF)), as well as training in a range of immunology, cellular and molecular biology techniques including single cell genomics. Mass cytometry is a significant innovation that takes advantage of the measurement resolution of Inductively Coupled Plasma (ICP) mass spectrometry and applies it to single-cell analysis. The cytometry time of flight (CyTOF®) "mass cytometer" provides for the first time, the ability to simultaneously quantitate at least 40 intracellular and extracellular parameters in individual cells.
The project will be carried out at the Kennedy Institute of Rheumatology, which is a world-renowned research centre housed in a new state-of-the-art facility in Oxford. The Institute houses basic and clinician scientists working on diverse aspects of immunology, inflammation and tissue biology and repair. The Kennedy Institute provides access to outstanding core facilitates including advanced imaging equipment, multiparameter cell sorting and analysis, mass cytometry, deep sequencing, a full histology core and bioinformatics infrastructure. The PhD programme includes a core curriculum of 20 lectures in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly group meetings, and will be expected to attend seminars in the department and relevant seminars in the wider University. Students will attend national and international meetings, at which they will present their data.
- Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol (2011) 11:738–49.
- Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, Pini M, Hainault I, Montastier E, Denis RG, Ancel P, Lacombe A, Ling Y, Allatif O, Cruciani-Guglielmacci C, André S, Viguerie N, Poitou C, Stich V, Torcivia A, Foufelle F, Luquet S, Aron-Wisnewsky J, Langin D, Clément K, Udalova IA, Venteclef N. Nat Med. 2015 Jun;21(6):610-8.
- Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development. Cole JE, Astola N, Cribbs AP, Goddard ME, Park I, Green P, Davies AH, Williams RO, Feldmann M, Monaco C. Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13033-8.
Immunology; Cardiovascular disease; Molecular, Cell and Systems Biology.