Kennedy Trust Prize Studentships
New pattern-recognition receptor signalling modalities in vascular inflammation
Pattern recognition receptors (PRR) such as toll-like receptors (TLR) are microbial and damage sensors that shape tissue-specific inflammatory responses. TLRs in cardio-vascular tissues and diseases (CVD) are expressed by a variety of vascular and immune cell types in the vessel wall.
TLRs have a very similar signaling modality to IL-1. Very recently an IL-1beta cytokine blocker has been shown to lower cardiovascular risks in patients surviving a heart attack, opening the way to a whole new range of therapeutic approaches targeting inflammation in cardiovascular disease, a major killer worldwide.
Our group has demonstrated that TLRs situated on the extracellular membrane such as TLR2 (1-2) are pro-atherogenic but the TLRs placed inside the cell such as TLR3 and TLR7 protect against atherogenesis and arterial injury (4). TLR signaling 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 during atherogenesis by identifying novel mechanism of signaling cross-talk between extracellular and intracellular TLRs and by dissecting cell-type specific roles in sensing molecular patterns. Aspects of cellular biology and/or single cell techniques and/or conditional deletion during atherogenesis will be prioritized to suit the individual interests of the candidate. Candidates are encouraged to get in touch to discuss the details of the project.
The Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility Training will be provided in a range of cell biology techniques, immune-assays, models of atherosclerosis, multicolour flow cytometry, and exciting new single cell platforms such as mass cytometry or CyTOF.
A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University such as the British Heart Foundation Centre of Excellence. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.
- 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.
- Cardiovascular disease
- Molecular, Cell and Systems Biology
Contact: Professor Claudia Monaco, Kennedy Institute of Rheumatology, University of Oxford.