NDORMS DPhil & MSc by Research
Dangerous immunity: investigating how toll-like receptors are activated by endogenous inflammatory signals
Inflammation is designed to protect us from infection and injury. Pathogenic molecules detected upon microbial invasion (pathogen associated molecular patterns, PAMPs) and host derived molecules generated upon tissue injury (damage associated molecular patterns, DAMPs) signal these dangers; their recognition by immune sensors such as toll-like receptors (TLRs) activates inflammatory signalling pathways. DAMPs are vital for our response to tissue injury in the absence of infection. However, these endogenous activators of inflammation are also major drivers of the persistent inflammation in autoimmune and metabolic diseases, and in tumors.
Whilst pathogen mediated immunity is increasingly well understood at the molecular level, it is not known how DAMPs activate TLRs, making rational drug design to target chronic sterile inflammation difficult. The extracellular matrix is a 3D network of secreted molecules that provides structural support to tissues and environmental signals that define the behaviour of resident cells. We recently identified how matrix molecules that are specifically expressed upon tissue damage can activate TLRs, driving persistent inflammation in a number of disease models.
This project will further examine how injury specific matrices orchestrate immunity and how this process goes awry in inflammatory diseases. Specific aims will undertake a systematic structure/function analysis of this fascinating family of matrix proteins to map TLR binding sites, and determine which inflammatory signalling pathways are activated downstream.
The Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility at the University of Oxford. Training will be provided in techniques including molecular and biochemical (PCR, cloning, site directed mutagenesis, siRNA, protein synthesis and purification), cellular (culture and stimulation of primary human immune cells, isolation of cells from patient tissues, ELISA) and bioinformatic/structural (evolutionary sequence analysis, modelling of 3D structures, crystallography) approaches.
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 and the Matrix Immunology Group, and also to attend external conferences to present their research globally.
Students will also have the opportunity to work closely with the crystallography team at the SGC and the nearby Diamond Light Source.
- Midwood, K.S., et al. (2009). Tenascin-C is an endogenous activator of TLR4 that promotes the maintenance of inflammation in arthritic joint disease. Nature Medicine. 15(7), 774-80.
- Piccinini, A.M. and Midwood, K.S. (2012) Endogenous Control of Immunity against Infection: tenascin-C regulates TLR4 mediated inflammation via microRNA-155. Cell Reports 2 (4): 914-926
- Montgomery AB, Kopec J, Shrestha L, Thezenas ML, Burgess-Brown NA, Fischer R, Yue WW, Venables PJ. (2015) Crystal structure of Porphyromonas gingivalis peptidylarginine deiminase: implications for autoimmunity in rheumatoid arthritis. Ann Rheum Dis. 2015 Jul 24.
- Yue WW, Froese DS, Brennan PE. (2014) The role of protein structural analysis in the next generation sequencing era. Top Curr Chem. 336:67-98