Alzheimer’s disease: Understanding the interaction of microglia risk genes
This research project is in competition for funding with one or more projects available through the UK Dementia Research Institute (DRI) at Cardiff. Usually the projects which receive the best applicants will be awarded the funding. Find out more information about the UK DRI and how to apply.
The aim of this project is to understand the interdependence of specific risk alleles and highlight the possibility of adjunctive therapies targeting different ‘arms’ of the immune cells to treat the disease.
Microglia, the immune cells of the brain, may be protective in Alzheimer’s disease, encircling amyloid plaques, clearing debris and limiting further inflammatory damage.
However, microglia can also be damaging in neuroinflammation, promoting inflammatory responses and causing neuronal damage. A weight of genetic evidence, much of which gained through GWAS study has implicated immune pathways in the development of Alzheimer’s disease.
How microglia contribute to the development of or protection from Alzheimer’s remains a subject of significant debate. Our aims is to use the human genetic data to guide mechanistic studies of the disease process to elucidate possible therapeutic approaches.
Continuing analysis of the functional consequences of risk and protective variants in human Alzheimer’s disease patients builds a picture from this mounting genetic evidence: defects in or hypofunction forms of activation receptors such as the R47H variant of TREM2 promote Alzheimer’s disease, whereas, defects in/hypofunction of inhibitory receptors, such as CD33 splice variants, protect from Alzheimer’s disease.
Project aims and methods
This PhD will mechanistically examine evidence of interaction between individual risk alleles leading to significantly enhanced risk of disease.
This PhD will involve training in lentiviral transduction of cell lines and primary microglia, use of conditional-immortalisation techniques, transcriptomic analysis of cell activation and single cell assessment of cell activation.
We have established a bank of reagents to analyse the interaction between specific risk genes, including mutated molecules, chimeric proteins, cellular assays, and gene knockin models of single nucleotide polymorphisms.
The research is well-funded, with the primary laboratory currently having in excess of £3M in active grant awards.
For further information on the type of research conducted in this project and at the UK Dementia Research Institute at Cardiff, see:
- Sims et al., 2017. “Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.” Nature Genetics 49:1373-1384.
- Davies et al., 2014. “The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal” Science 344:645-648.
A minimum of a 2.1 or master's in a relevant degree subject is required. Relevant degrees subjects include, for example:
- cell biology
- and related disciplines.