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PhD in Dementia Research - Alzheimer’s disease: Understanding the interaction of microglia risk genes


Project Description

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.
This PhD will mechanistically examine evidence of interaction between individual risk alleles leading to significantly enhanced risk of disease. The aim of the study 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.
The studentship 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.

Supervisors: Prof Philip Taylor and Dr. Emyr Lloyd-Evans
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.

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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