PhD project

Supervisor: Sally A. Cowley

Microglia are brain parenchyma-resident macrophages, with important homeostatic functions, clearing away dead cells and debris, and remodelling defunct neuronal connections. They are strongly implicated in the progression of Alzheimer’s and other neurodegenerative diseases, with several key Alzheimer’s-associated genes expressed not in neurons but specifically in microglia. We have pioneered methods for differentiating authentic human microglia from pluripotent stem cells, which are used widely to investigate disease pathogenesis and identify new therapeutic targets[1-5]. You will use human iPS-microglia to investigate the role of one of these neurodegenerative disease-associated genes. Using CRISPR/Cas9 technologies to knockout genes and/or introduce precise mutations or reporters, you will be able to dissect the molecular interactions and regulatory pathways through which these genes mediate neuroinflammation and disease progression.

Keywords:

• Biochemistry, Cell Biology / Development, Genetics, Immunology, Molecular Biology, Neuroscience / Neurology, Pathology

Publications:

• Washer, S.J., et al., Single-cell transcriptomics defines an improved, validated monoculture protocol for differentiation of human iPSC to microglia. Scientific Reports, 2022. 12(1): p. 19454.
• Lee, H., et al., LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages. Stem Cell Reports, 2020. 14(5): p. 940-955.
• Hall-Roberts, H., et al., TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to knockout, yet only subtle functional phenotypes in human iPSC-derived macrophages. Alzheimer’s Research & Therapy, 2020. 12(1): p. 151.
• Hedegaard, A., et al., Honing the Double-Edged Sword: Improving Human iPSC-Microglia Models. Front Immunol, 2020. 11: p. 614972.
• 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.