About the Project
Supervisors: Dr Heather Wilson, Dr Mirela Delibegovic and Professor Robert Barker
Macrophages are a key feature in all types of tissue injury including atheroma, cancer, diabetes and inflammatory diseases. In each of these settings they can be activated to cause further injury (M1 macrophage) or to repair damage (M2 macrophage) (1, 2). Understanding the factors that control macrophage activation is one of the critical challenges facing those who want to develop new therapies for inflammatory disease. Macrophage phenotypes are controlled by cytokines and inflammatory mediators, which are in turn regulated by the intracellular regulators, Suppressors of Cytokine Signalling (SOCS) proteins (3). Key findings from our published work and novel preliminary data in rodent macrophages have identified SOCS3, a major physiological regulator of cell signalling, as an important target molecule (4,5,6). We have shown that SOCS3 drives the tissue destructive properties of macrophages and modulates their phagocytic capacity, two important processes in the inflammatory response. We are now in a unique position to expand these findings and address our hypothesis that manipulation of human macrophages via SOCS3 can reduce their pro-inflammatory properties in vivo and translate into important new therapies to treat susceptible patients. Using a range of molecular, cellular and immunological techniques, including siRNA technology, qPCR, macrophage culture, ELISAs, microscopy and imaging, the aim is to perform translational experiments to test this directly.
Funding Notes
This project is part of a competition funded by the Institute of Medical Sciences. Full funding is available to UK/EU applicants only. International candidates are welcome to apply but may need to provide their own funding of approximately £12,000 per annum to meet the difference between UK and Overseas fees.
Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Distinction at Masters level.
References
1 Murray, P. J., and Wynn, T. A. (2011). Protective and pathogenic functions of macrophage subsets. Nature Rev. Immunol. 11, 723–737.
2. Wilson, HM. (2010) Macrophages heterogeneity in atherosclerosis - implications for therapy. J Cell Mol Med.
3. Wilson HM. SOCS Proteins in Macrophage Polarization and Function. Front Immunol. 2014 Jul 28;5:357.
4. Liu, Y, Stewart, KN, Bishop, ET, Marek, CM, Kluth, DC, Rees, AJ, Wilson, HM. (2008) Unique expression of Suppressor of Cytokine Signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo. J Immunol. 180, 6270-78.
5. Whyte CS, Bishop ET, Rückerl D, Gaspar-Pereira S, Barker RN, Allen JE, Rees AJ, Wilson HM. Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. J Leukoc Biol. 2011 Nov;90(5):845-54
6. Arnold CE, Whyte CS, Gordon P, Barker RN, Rees AJ, Wilson HM, A critical role for SOCS3 in promoting M1 macrophage activation and function in vitro and in vivo. Immunology 2014;141:96-110.
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