NDORMS DPhil & MSc by Research
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 Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility at the University of Oxford. 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.
Training will be provided in techniques including models of atherosclerosis and state-of-the-art single cell platforms (e.g. mass cytometry (CyTOF)), as well as a range of immunology, cellular and molecular biology techniques, and 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.
A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. Students will attend weekly seminars within the department and those relevant in the wider University. Students will be expected to present data regularly to the department, the Cardiovascular Inflammation Group and to attend external conferences to present their research globally. Students will also have the opportunity to work closely with the Genomics of Inflammation Group.
- 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.
- Cardiovascular disease
- Molecular, Cell and Systems Biology