Research interests/description of main research theme:
Applications are invited for a 3-year fully-funded PhD Studentship starting in October 2023 in the laboratory of Dr Martin Higgs at the University of Birmingham https://www.birmingham.ac.uk/research/cancer-genomics/research/lysine-methylation-dna-damage/index.aspx This is funded as part of a BRC National Paediatric Excellence Initiative supported by the NIHR GOSH Biomedical Research Centre (see below)
Many rare human diseases are characterised by deficiencies in neuronal genome stability. However, research into these diseases is hampered by patient sample availability and/or viable animal models. The generation of induced pluripotent stem cells (iPSCs), the use of CRISPR-Cas9 gene editing and the establishment of iPSC-derived neurons now provides a powerful genetic tool to study the causative mutations of these diseases in an isogenic background. This studentship aims to establish a robust genetic disease modelling platform using these techniques to study the pathogenic basis of these diseases.
Using exemplar models of DNA damage and repair disorders linked to neuropsychiatric and neurodevelopmental syndromes, the student will first use CRISPR-Cas9 to introduce selected patient mutations or loss-of-function alleles into wild-type iPSCs, or to correct patient-associated disease-causing mutations. These iPSCs will then be derived into neural stem cells and then neurons using well established techniques. Once established, the DNA repair capacity and/or transcriptional profile of these iPSC-derived neurons will be examined using a combination of immunofluorescence, comet assay, ChIP, RNA-seq and flow cytometry/ELISA.
This studentship will provide a broad range of training opportunities as well as the opportunity to exchange knowledge between multiple groups both at UoB and GOSH. It will lay the groundwork for a phenotypic profiling platform for the pathophysiological study of these diseases in isogenic systems in relevant cell types.
The NIHR GOSH Biomedical Research Centre (BRC)
This studentship is funded by the NIHR GOSH BRC, which is a partnership between Great Ormond Street Hospital and the University College London (UCL) Great Ormond Street Institute of Child Health (ICH). In July 2022, the NIHR awarded BRC status to the GOSH BRC for a fourth term, which runs from December 2022 to November 2027. As part of this, a wider national collaboration - a BRC National Paediatric Excellence Initiative - has been set up between GOSH BRC and children’s hospitals in Birmingham, Sheffield and Liverpool.
The GOSH BRC has five main research themes:
1. Gene, Stem and Cellular Therapies (GSCT)
2. Genomic Medicine (GM)
3. Accelerating Novel Therapies (ANT)
4. Tissue Engineering and Regenerative Medicine (TERM)
5. Applied Child Health Informatics (ACHI)
This studentship sits within the Accelerating Novel Therapies (ANT) theme. This aims to advance novel precision therapies to clinical translation and eventual licensing as standardised treatments within the NHS and globally, by delivering clinical trials and stem-cell based evaluation of therapies. It also supports the development of new diagnostics/biomarkers to aid monitoring of the progress of paediatric rare diseases and increase our understanding of the safety and efficacy of treatments.
Person Specification
Applicants should have a strong background in biological sciences, and ideally a background in cellular and molecular biology. They should be able to demonstrate prior competence in a laboratory environment. They should have a strong commitment to research in genome stability, neurology or neurogenetics and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Biomedical Sciences, Biochemistry, Neurology or Cellular Biology.
How to apply
Informal enquiries should be directed to Dr Martin Higgs ([Email Address Removed]).
Applications should be made online via the University of Birmingham online portal (weblink TBC). To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.
Shortlisted applicants will be required to attend an interview in mid/late March 2023. This will include meeting the research group and a tour of the labs.