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Characterising DNA damage repair in Huntington’s disease

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.

This is an exciting opportunity to help define the molecular mechanism of Huntington’s disease (HD).

Background

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.

Project aims and methods

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.

Academic criteria

A minimum of a 2.1 or master's in a relevant degree subject is required. Relevant degree subjects include:

  • neuroscience
  • biochemistry
  • biology/biomedical sciences.

Supervisors

Professor Lesley Jones

Professor Lesley Jones

Professor, Division of Psychological Medicine and Clinical Neurosciences

Email:
jonesl1@cardiff.ac.uk
Telephone:
+44 (0)29 2068 8469

Co-supervisors

Professor Vincent Dion and Dr Tom Massey

Programme information

For programme structure, entry requirements and how to apply, visit the Medicine programme.

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