Microglial NFAT signalling and Alzheimer’s disease genetic risk networks
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.
In this project, you will develop skills in molecular biological, cell culture, genome biology and bioinformatics.
Genome-wide association studies (GWAS) have identified robust risk loci for Alzheimer’s disease (AD). These findings serve as a starting point for novel biological investigation and treatment strategies.
However, heritability is mediated in a polygenic fashion, involving thousands of alleles/genes across the genome. A major challenge is to understand how risk genes act together to bring about cellular dysfunction.
We have recently identified microglial transcriptional networks that account for a substantial proportion of the common variant heritability of AD, suggesting that risk genes share gene regulatory properties (read the publication to find out more). This project will build on these findings to investigate the role of microglial NFAT transcription factors as transducers and regulators of AD risk.
NFAT transcription factor activity is calcium ion dependent, and has been shown to be induced upon activation of TREM2, a major AD risk gene (read the publication to find out more).
Furthermore, NFAT is positioned downstream of other AD risk genes (eg PLCG2 and PTK2B) - read the publication to find out more. NFAT activity is therefore well positioned as a potential transducer of AD risk pathways.
Project aims and methods
This PhD will use molecular and genomic approaches to investigate the function and regulation of NFAT activity in microglia, forming three specific aims:
- define the genomic targets of selected NFAT family members genome-wide (e.g. using ChIP-seq)
- investigate the relationship between NFAT targets and genetic risk for AD
- identify novel chemical and protein regulators of NFAT activity
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.