Background:
Why do some cells age too early? Hutchinson–Gilford Progeria Syndrome (HGPS) is a genetic disorder that causes premature ageing and leads to an average life expectancy of 15 years. It results from a mutation in the nuclear lamina gene LMNA, which compromises the mechanical integrity of the nucleus. Our recent findings show that HGPS patient cells experience abnormally high cytoskeletal tension, making their nuclei mechanically fragile and prone to DNA damage.
In healthy cells, mechanical feedback between the nucleus and cytoskeleton prevents damaging levels of force. We have discovered that this protective pathway involves two key proteins—Sun2, located in the nuclear envelope, and Rnd3, a regulator of actomyosin tension. When forces rise, Sun2 and Rnd3 coordinate to reduce tension and safeguard the genome. In HGPS cells, this feedback loop fails, leading to persistent stress, nuclear rupture, and cell death.
Objective:
Explain the mechanism behind the mechanical vulnerability of HGPS patient cells.
Experimental Approach:
We have identified a nucleus-based negative feedback loop for actomyosin contractility that has the potential to safeguard against DNA damage and have developed methods to interrogate nuclear organisation and DNA/chromatin damage. You will:
- Identify why the mechanism of controlling actomyosin tension is defective in HGPS cells: You will investigate the localisation/turnover of Sun2 and Rnd3 in HGPS patient cells using protein biochemistry and live-cell super resolution microscopy of cells subject to mechanical force.
- Investigate the impact of excessive actomyosin forces on DNA and chromatin damage in HGPS patient cells: HGPS patients have high levels of DNA damage. You will investigate whether the excessive actomyosin force is causative of the mutational load and observed chromatin remodelling in the disease
- HGPS skin model: You will generate established organotypic HGPS cell-based skin models and test whether reduced actomyosin contractility can rescue nuclear HGPS pathology.
Training and Environment:
You will join two established research groups that work on separate aspects of mechanobiology of the nucleus in ageing and disease. The two labs will give you an excellent experimental and theoretical introduction into the interdisciplinary fields and quantitative biology skills that we are employing in this project. In the Toseland laboratory, you will learn the techniques required for quantitative analysis of chromatin and nuclear envelope remodelling with a particular emphasis on employing methodology for super-resolution imaging and single molecule tracking in the nucleus. In the Zech laboratory, you will learn state-of-the-art live cell imaging techniques such as live cell stretching and compression, FRET and FRAP. You will learn to quantitatively analyze microscopy and biochemical assays. Findings will be translated into organotypic skin models.
This project is ideal for students with backgrounds in biochemistry, cell biology, biophysics, or biomedical engineering who are excited by interdisciplinary research at the interface of physics and cell biology.
We are committed to supporting the career development of our students, encouraging attendance at both international and UK meetings, conferences and training courses to develop your research skills and interests.
Please also see our websites for research interests:
Institutional entry requirements for PhD:
Applicants for postgraduate research study at Liverpool are normally expected to hold a UK first degree with a First Class or Upper Second Class degree classification, or a Second Class degree plus a Master’s degree. Equivalent international qualifications are also accepted, and their equivalence will be evaluated on the basis of the information provided by the European Network of Information Centres (ENIC) formerly NARIC as well as internal guidance based on our experience of a qualification’s suitability as a preparation for our programmes.
For applicants whose first language is not English, an IELTS score of 6.5 with no band score lower than 5.5, or an equivalent University of Liverpool acceptable English language qualification. For further details and other acceptable English language qualifications please see here: http://www.liv.ac.uk/study/international/countries/english-language/
How to apply:
All applications are made via the application form accessed on the DiMeN website at www.dimen.org.uk
Please read the full application guidance on the website before submitting an application.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
