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 observed that IRF5 deficiency reduces size of atherosclerotic lesions and selectively ablates a CD11c+ macrophage subset in the aorta (3), 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.
Expected value of results
The worldwide use of statins and the recent advances in hypolipidemic drugs such as PCSK9 inhibitors together with an unprecedented epidemic of obesity and diabetes are predicted to shift the traditional risk profile of patients with CVD towards metabolic diseases. We hypothesize that IRF5, by driving a subset of pathogenic CD11c+ macrophages, is the missing link between metabolic inflammation and atherosclerosis explaining the clinical clustering of these afflictions. The project will further our understanding of the increased risk of atherosclerosis in patients with metabolic diseases such as obesity and insulin resistance and it will explore the fundamental molecular mechanisms regulating macrophage programming in metabolic inflammation. Therefore, we anticipate that new therapeutic approaches that control inflammation in atherosclerosis (via targeting a pathogenic macrophage population) may emerge from this work.
- 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.
- Seneviratne AN, Edsfeldt AO, Cole JE, Kassiteridi C, Swart M, Park I, Green P, Khoyratty TE, Saliba DG, Goddard ME, Sansom SN, Goncalves I, Krams R, Udalova IA, Monaco C. Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis. Circulation. 2017 Jul 11. pii: CIRCULATIONAHA.117.027844. doi: 10.1161/CIRCULATIONAHA.117.027844. [Epub ahead of print]
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 genomics.
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 led by Professor Irina Udalova. Students will also have the opportunity to present their research and interact with researchers within the British Heart Foundation Centre of Excellence in Oxford.
How to Apply
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Graduate Studies Officer, Sam Burnell (Samuel.firstname.lastname@example.org) who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system.
The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.
For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford
Contact: Professor Claudia Monaco, Kennedy Institute of Rheumatology, University of Oxford