NDORMS DPhil & MSc by Research
New pattern-recognition receptor signalling modalities in vascular inflammation
Cardiovascular disease (CVD) is the most common cause of global mortality and its incidence is expected to grow worldwide. Atherosclerosis, a multifactorial chronic inflammatory disease of the large and medium-sized blood vessel, is largely responsible for CVD and stroke. For decades, the aetiology of atherosclerosis was mainly attributed to accumulation of cholesterol in the intima, the innermost layer of the vessel wall, resulting in narrowing of the artery. However, a number of studies over last two decades have demonstrated that atherosclerosis is a chronic inflammatory disease with a much more complex pathophysiology. Very recently anti-inflammatory approaches in particular, with an IL-1 cytokine blocker have shown to lower cardiovascular risks in patients surviving a heart attack, opening the way to a whole new range of therapeutic approaches targeting inflammation (1).
Pattern recognition receptors (PRR) such as toll-like receptors (TLR) and C-type lectins (CLR) are microbial and damage sensors that shape tissue-specific inflammatory responses. TLRs have a very similar signaling modality to IL-1. Modified lipoproteins arising in conditions of hypercholesterolemia activate TLR2 and TLR4, and deletion of these receptors reduces atherogenesis in mice. Our group has shown that inflammation in human atherosclerotic lesions is selectively driven by TLR2 via MyD88 and NFκB (2-3). However we also found that the endosomal receptors TLR3 and TLR7 protect against atherogenesis and arterial injury (4). This suggests that complex mechanisms of pattern recognition occur in the vasculature.
TLR signalling can either be protective or detrimental in atherosclerosis depending on the sensing (extracellular vs. endosomal) compartment. The aim of this project is to deconstruct pattern recognition events in the vascular wall prior and during atherogenesis 1) by dissecting cell-type specific roles in sensing in models of atherosclerosis and 2) by identifying novel mechanism of signaling cross-talk between extracellular and intracellular TLRs. In this context we will explore whether the intracellular compartmentalization of signalling affects the crosstalk between endosomal and extracellular TLRs.
- Novartis. Novartis Phase III study shows ACZ885 (canakinumab) reduces cardiovascular risk in people who survived a heart attack. 2017 [cited 2017 12 June]; Available from: https://www.novartis.com/news/media-releases/novartis-phase-iii-study-shows-acz885-canakinumab-reduces-cardiovascular-risk.
- Monaco C., Andreakos E., Kiriakidis S., Mauri C., Bicknell C., Foxwell B., Cheshire N., Paleolog E., Feldmann M. The canonical pathway of NFκB activation selectively regulates pro-inflammatory and pro-thrombotic responses in human atherosclerosis. PNAS USA 2004, 2004 13;101:5634-9.
- Cole JE, Navin TJ, Cross AJ, Goddard ME, Alexopoulou L, Mitra AT, Davies AH, Flavell R, Feldmann M, Monaco C. An unexpected protective role for TLR3 in the arterial wall. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2372-7. Comment on PNAS USA 2011; 108 (7): 2637-8.
- Monaco C, Gregan S, Navin T, Davies AH, Feldmann M. TLR-2 drives inflammation and matrix degradation in human atherosclerosis Circulation 2009; 120: 2462-2469.
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 (ELISA, flow cytometry), tissue specific gene targeting in models of atherosclerosis, and cellular and molecular biology techniques (cell culture, siRNA, fusion proteins, western-blot, immunoprecipitation, immunofluorescence, PLA), imaging (epifluorescence microscopy, confocal microscopy, FRET, BRET).
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 present their research and interact with researchers within the British Heart Foundation Centre of Excellence in Oxford.
Contact: Professor Claudia Monaco, Kennedy Institute of Rheumatology, University of 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 (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 2018.
When completing the online application, please read the University Guide.