Last Date: Friday, December 13, 2024
Supervisors: Dr A Vincent, Dr P Actis, Prof Gavin Hudson
Competition Funded PhD Project (Students Worldwide)
Newcastle University MRC DiMeN Doctoral Training Partnership
About the Project:
Mitochondrial DNA (mtDNA) deletions accumulate with age in diseased and ageing muscle. Recent work has demonstrated that these mtDNA deletions appear to initially accumulate in small focal regions adjacent to the nuclei in human tissues, as evidenced by these being the smallest regions of detectable mitochondrial dysfunction. The work further demonstrated a high mtDNA deletion load, copy number, mitochondrial mass and an increase in mitonuclear signaling proteins in these regions. A system to mechanistically study and modify this process has been lacking. However recently we have developed a 3D muscle on a chip model for mitochondrial myopathy.
Nanobiopsy developed has recently been used to biopsy and sequence single mitochondrion mtDNA and has also been shown to have utility in transfer of organelles between cells.
Your project will aim to:
1) Development of a culture based model, utilizing nanobiopsy to transplant wild type and mutant mitochondria into different subcellular locations and track their mitochondrial dynamics. To answer the question does proximity to the nucleus matter?
2) Modify key cellular drivers in this process, such as mito-nuclear signalling, mitophagy, mitochondrial transport and dynamics, to answer the question can we modify this process?
You will be supported by the Newcastle and Leeds team to apply novel technology to build on recent findings in mitochondrial disease pathology.
You will use a 3D muscle culture model with and without mtDNA mutations. You will employ nanobiopsy to transplant mitochondria with and without mutations into a healthy cultured muscle at different subcellular locations. You will learn how to fluorescently tag the mitochondrion so that you can follow the mitochondrion post-transplant using live cell imaging. You will learn how to culture the cells and then sequence the mtDNA and quantify mtDNA heteroplasmy to understand the impact of cellular location on the accumulation of mtDNA mutations. You will modify different cellular process e.g mitophagy and mitochondrial dynamics using known compounds and siRNA respectively, to understand the impact on mitochondrial genetics.
This is an exciting project at the forefront of biological sciences and we are very excited to share this journey with you.
Training and environment:
You will get an unique multidisciplinary training in molecular biology, nanotechnology and bioinformatics. Situated within the world leading mitochondrial research group at Newcastle University the student will be part of a large and vibrant cohort of PhD students. You will have the opportunity to spend portion of your PhD working at Leeds with Dr Actis as well as in Newcastle with Dr Vincent and Prof Hudson. Both Universities have excellent training opportunities that add to the opportunities provided by DiMeN. This supervisory team all have a strong track record of developing and supporting PhD students as well as a history of prior collaboration together. The supervisory team will develop you to become an independent researcher equipping them with experimental design, analytical and critical thinking skills, academic writing and publishing experience, including opportunities to participate in peer review. We will identify suitable training opportunities to supplement the training provided to the DiMeN cohort and ensure they have ample opportunity to present their work and publish.
Supervisors:
Dr Amy Vincent X: @AmyV91
Dr Paolo Actis X: @paoloactis
Prof Gavin Hudson: @DrPerscitus
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 how to apply can be found on our website:
Funding Notes:
Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£19,237 for 2024/25) and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: View Website
Studentships commence: 1st October 2025
Good luck!
References:
Nanobiopsy investigation of the subcellular mtDNA heteroplasmy in human tissues”. (2024). Scientific Reports. 14:13789. https://www.nature.com/articles/s41598-024-64455-0
“Clonally Expanded mtDNA Deletions in Human Skeletal Muscle Originate as a Proliferative Perinuclear Niche” (2018) Annals of Neurology 84(2):289-301. https://onlinelibrary.wiley.com/doi/10.1002/ana.25288
“Understanding mitochondrial DNA maintenance disorders at a single cell level”. (2019) Nucleic Acids Research. 47(14):7430-7443. https://academic.oup.com/nar/article/47/14/7430/5506853
“Single molecule delivery into living cells”. (2024). Nature Communications. 15 (1):4403
“Single-cell nanobiopsy enables multigenerational longitudinal transcriptomics of cancer cells”. (2024). Science Advances. 10 (10):eadl0515 https://www.science.org/doi/10.1126/sciadv.adl0515
“A subcellular cookie cutter for spatial genomics in human tissue”. (2022). Analytical and Bioanalytical Chemistry 414 (18):5483-5492 https://link.springer.com/article/10.1007/s00216-022-03944-5
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