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PhD in Dementia Research - Characterising DNA damage repair in Huntington’s disease


Project Description

This is an exciting opportunity to help define the molecular mechanism of Huntington’s disease (HD). HD is an incurable neurodegeneration caused by an expanded CAG repeat in the HTT gene. Longer CAG repeats reduce the age of onset of disease, and genetic variation in the DNA damage repair also alters age of disease onset. It is likely that the variation in DNA damage repair leads to expansion of the repeat in somatic cells, especially in neurons, and that DNA damage repair genes and variants cause faster CAG repeat expansion, precipitating HD pathophysiological changes. We have cell culture systems with long CAG repeats that show the expanded CAG phenotype. We wish to build CRISPR/Cas9 knock out pooled and arrayed libraries against the main hits discovered by our analysis to be possible modifiers in patients. These hits include many known DNA damage repair genes as well as potentially novel genes, and we will use our cell culture systems to identify which of our potential genetic hits can affect expansion of the CAG repeat, and the direction of any change. We will assay the downstream effects of these modifiers using state-of-the art assays for CAG repeat length change, mitochondrial metabolism, and DNA damage. Potential hits will be then examined in induced pluripotent stem cells from HD patients and their derived neurons. Small molecule inhibitors of relevant DNA damage repair processes revealed by the screening will be used to probe relevant mechanisms.

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

This is a collaboration between the UK DRI at Cardiff University and the UK DRI at the University of Cambridge

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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