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PhD in Dementia Research - Microglial NFAT signalling and Alzheimer’s disease genetic risk networks

  • Full or part time
  • Application Deadline
    Sunday, March 31, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

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 1000s 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 AD1, suggesting that risk genes share gene regulatory properties. 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 TREM22, a major AD risk gene. Furthermore, NFAT is positioned downstream of other AD risk genes3 (e.g. PLCG2 and PTK2B). NFAT activity is therefore well positioned as a potential transducer of AD risk pathways. This PhD will use molecular and genomic approaches to investigate the function and regulation of NFAT activity in microglia, forming three specific aims:
1. Define the genomic targets of selected NFAT family members genome-wide (e.g. using ChIP-seq).
2. Investigate the relationship between NFAT targets and genetic risk for AD
3. Identify novel chemical and protein regulators of NFAT activity
The student will develop skills in molecular biological, cell culture, genome biology and bioinformatics.
1. Tansey, K. E., Cameron, D. & Hill, M. J. Genetic risk for Alzheimer’s disease is concentrated in specific macrophage and microglial transcriptional networks. Genome Medicine 10, 14 (2018).
2. Hsieh, C. L. et al. A Role for TREM2 Ligands in the Phagocytosis of Apoptotic Neuronal Cells by Microglia. J Neurochem 109, 1144–1156 (2009).
3. Thankam, F. G., Dilisio, M. F., Dougherty, K. A., Dietz, N. E. & Agrawal, D. K. Triggering Receptor Expressed on Myeloid Cells and 5′Adenosine Monophosphate-activated Protein kinase in the Inflammatory Response: A Potential Therapeutic Target. Expert

Funding Notes

The funding for the studentship is provided by the UK Dementia Research Institute at Cardiff. Funding is in competition with 5 projects advertised, and an anticipation to fund 3.
Full UK/EU tuition fees
Doctoral stipend matching UK Research Council National Minimum.
Additional funding is available over the course of the programme and will cover costs such as research consumables and training.

Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject.
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

References

The duration of the PhD will be 3.5 years
In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert)
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2019). This will take you to the application portal.
In order to be considered candidates must submit the following information:

• Supporting statement
• CV
• Qualification certificates
• References x 2 (references are optional but will strengthen your application)
• Proof of English language (if applicable)

In the 'Research proposal and Funding' section of your application, please specify the project title and supervisors of the project and copy the project description in the text box provided.
Please select 'No, I am not self-funding my research' when asked whether you are self-funding your research.
In the funding section, please select "I will be applying for a scholarship / grant" and specify that you are applying for advertised funding from UK DRI.

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