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Exploring Parkinson’s related gene function in hiPS-macrophages and microglia

  • Full or part time
    Prof W S James
    Dr S Cowley
  • Application Deadline
    Friday, January 10, 2020
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

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. We have developed a genetically tractable system for differentiating authentic human tissue macrophages, especially microglia, from pluripotent stem cells, which is used widely to investigate disease pathogenesis and develop new therapies [1, 2]. Many Parkinson’s disease-associated genes are expressed in macrophages/microglia (notably LRRK2, a-synuclein, GBA, PINK1), and in the case of disease-associated variants, this leads to neuroinflammation [3, 4]. You will use human iPS cells to investigate the role of one of these genes in macrophage/microglia. Using the latest CRISPR/Cas9 technology to Knockout and/or introduce precise mutations, you will be able to dissect the molecular interactions and regulatory pathways through which these genes mediate immune dysfunction.

Funding Notes

4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£17,009 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. Haenseler, W., 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, 2017. 8(6): p. 1727-1742.
2. van Wilgenburg, B., et al., Efficient, long term production of monocyte-derived macrophages from human pluripotent stem cells under partly-defined and fully-defined conditions. PloS one, 2013. 8(8): p. e71098.
3. Lee, H., W. James, and S. Cowley, LRRK2 in peripheral and central nervous system innate immunity: its link to Parkinson's disease. Biochemical Society transactions, 2017. 45(1): p. 131-139.
4. Lee, H., et al., LRRK2 is recruited to phagosomes and co-recruits Rab8 and Rab10 in human pluripotent stem cell-derived macrophages. bioRxiv, 2019: p. 779835.

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FTE Category A staff submitted: 223.80

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