PhD Regulation of the antiviral and neuroinflammatory states of human tissue macrophages

Closing Date

11 Jan 2019

Salary

£16,777

Address

Sir William Dunn School of Pathology, University of Oxford

Duration

4 years

Project Description

The macrophage is an evolutionarily ancient sentinel of the health of all of the body’s tissues: clearing away dead cells and debris; as brain-resident microglia, remodelling defunct neuronal connections; nurturing tissue stem cells; detecting and responding to pathogens. All successful pathogens have to have mechanisms for overcoming macrophage defences, and many of the chronic diseases of ageing stem from the overloading of tissue macrophage clearance systems. The result of such processes is tissue damage, inflammation, morbidity and even death. We have developed a genetically tractable system for differentiating authentic human tissue macrophages from pluripotent stem cells that is used widely to investigate disease pathogenesis and develop new therapies in academic and commercial laboratories around the world. You will use this system to investigate the role of specific genes that are hypothesized to play key roles in switching macrophages from a homeostatic to an inflammatory state, or in resistance to infection by viruses such as HIV and Zika virus. By using the latest CRISPR/Cas9 technology to Knockout and/or introduce precise mutations into genes of interest, you will be able to dissect the molecular interactions and the regulatory pathways underlying the macrophage response to pathogenic signals.

Funding Notes

4 Year DPhil Prize Studentships cover University and College fees, a stipend of ~£16,777 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

1. Karlsson KR, Cowley S, Martinez FO, Shaw M, Minger SL, James W. Homogeneous monocytes and macrophages from human embryonic stem cells following coculture-free differentiation in M-CSF and IL-3. Exp Hematol. 2008;36(9):1167–75. 
2. Van Wilgenburg B, Moore MD, James WS, Cowley SA. The productive entry pathway of HIV-1 in macrophages is dependent on endocytosis through lipid rafts containing CD4. PLoS One. 2014;9(1):e86071. 
3. van Wilgenburg B, Browne C, Vowles J, Cowley SA. Efficient, Long Term Production of Monocyte-Derived Macrophages from Human Pluripotent Stem Cells under Partly-Defined and Fully-Defined Conditions. Covas DT, editor. PLoS One [Internet]. 2013 Aug 12 [cited 2018 May 15];8(8):e71098. Available from: http://dx.plos.org/10.1371/journal.pone.0071098 
4. Haenseler W, Sansom S, Buchrieser J, Newey S, Moore C, Nicholls F, et al. A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response. Stem Cell Reports [Internet]. 2017;8(6):1727–42. Available from: http://dx.doi.org/10.1016/j.stemcr.2017.05.017 
5. Buchrieser J, James W, Moore MD. Human Induced Pluripotent Stem Cell-Derived Macrophages Share Ontogeny with MYB-Independent Tissue-Resident Macrophages. Stem Cell Reports. 2017;8(2):334–45. 
6. Flynn R, Grundmann A, Renz P, Hänseler W, James W, Cowley S, et al. CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells. Exp Hematol [Internet]. 2015;43(10):838–48.