About the Project
Project Overview:
Macrophages are versatile cells that orchestrate both the induction and the resolution of inflammation. Mis-regulated macrophage function is the hallmark of a wide range of autoimmune and metabolic diseases, and tumors. However, the factors that control the behaviour of these cells are not yet well defined.
Macrophages can be driven towards an aggressive pro-inflammatory phenotype, or a tissue repair phenotype, by specific differentiation protocols in vitro. However, a much larger spectrum of macrophage subsets exists in vivo. The microenvironment of these cells is key to defining their behaviour; not only the surrounding cocktail of soluble cues (including cytokines, growth factors and microbial products), but also the tissue location of the macrophage impacts its function.
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 changes in the matrix during inflammation affect macrophage behaviour, enabling them to proliferate and thrive, and mediate tissue destruction and repair. This project will further examine how tissue specific matrices can imprint macrophage phenotype and how this process goes awry in inflammatory diseases and in tumors.
Specific aims will: 1) define the impact of tenascin-C, a matrix glycoprotein specifically induced upon tissue injury and infection, and persistently overexpressed in many inflammatory diseases and cancers, on macrophage phenotype and 2) investigate the molecular mechanisms by which tenascin-C controls macrophage activation.
For further information: please contact Prof. Kim Midwood in the first instance:
Email: [Email Address Removed]
Website: http://www.kennedy.ox.ac.uk/research/group/kmidwood
Training:
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 biochemical, cellular and molecular techniques including PCR, cloning, site directed mutagenesis, si and shRNA, recombinant protein synthesis and purification, culture of primary human immune cells, 3D micromass culture models, time lapse and intra-vital microscopy, and in vivo disease models.
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 Matrix Immunology Group and to attend external conferences to present their research globally.
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 Directors of Graduate Studies 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 2017.
When completing the online application, please read the University Guide: https://www.ox.ac.uk/admissions/graduate/applying-to-oxford/application-guide?wssl=1
References
Recommended Reading:
1. Hallmarks of cancer: the next generation (2011) Hanahan, D and Weinberg RA. Cell 4;144 (5):646-74.
2. Macrophage activation and polarization: nomenclature and experimental guidelines (2014) Murray, P.J. et al. Immunity. 41(1):14-20
3. Tenascin-C is an endogenous activator of TLR4 that promotes the maintenance of inflammation in arthritic joint disease. (2009) Midwood, K.S., et al. Nature Medicine. 15(7):774-80.
4. Distinct microenvironmental cues trigger divergent TLR4-mediated immune signalling in macrophages (2016) Piccinini, A.M., Zuliani-Alvarez, L., Lim, J.M.P and Midwood, K.S. Science Signalling. In press.
5. IRF controls both acute and chronic inflammation. (2015) Weiss M, Byrne AJ, Blazek K, Saliba DG, Pease JD, Perocheau D, Feldmann M, Udalova IA.PNAS. doi:10.1073/pnas.1506254112.
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