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MRC DiMeN Doctoral Training Partnership: Mitochondrial DNA mutations in blood: Why do they decline?


Project Description

Mitochondrial diseases are caused by mutations in nuclear and mitochondrial (mt) genomes and there is currently no cure for these debilitating disorders. Individuals carrying the most prevalent heteroplasmic mtDNA mutation, m.3243A>G, display a wide range of phenotypes from clinically silent to severe neurodegeneration. Disease severity is partly explained by the proportion of mutated mtDNA molecules (heteroplasmy) but the relationship is complicated, making patient counselling challenging. In mitotic tissues (e.g. blood), m.3243A>G heteroplasmy declines over time. The mechanism behind this process is currently unknown; it is thought to be linked to the number of divisions a cell has undergone but intracellular negative selection may also play a role. Understanding this process could lead to the identification of new therapeutic targets.

This project will use fluorescence activated cell sorting to separate blood into subpopulations representing the major leukocyte developmental stages. m.3243A>G heteroplasmy and mtDNA copy number will be measured by pyrosequencing and real-time PCR. Within T cells, which have the longest mitotic history and lowest heteroplasmy, there is likely to be heterogeneity among individual cells. Single T cells will be tracked and expanded into clones, allowing the student to correlate heteroplasmy with mitotic history and manipulate the number of cell divisions by stimulating proliferation in vitro. Using clinical data, the student will model the relationship between cellular sub-population heteroplasmy and disease burden. To investigate the role of active intracellular selection in declining levels, cells will be cultured in conditions designed to manipulate reliance on oxidative phosphorylation.

Based at the Wellcome Centre for Mitochondrial Research at the Faculty of Medical Sciences, Newcastle University, the student will be part of a thriving, multidisciplinary and collaborative research environment with a mission to transform the lives of patients with mitochondrial disease. The supervisory team combines expertise in mitochondrial genetics, mitochondrial biology, immunology and haematopoiesis and will provide training in a wide variety of cellular, molecular genetic and statistical techniques. The project has the potential to identify new therapeutic targets and to provide a better prognostic test for patients, allowing clinicians to tailor clinical advice and treatment.

Supervisors:
Dr. Sarah Pickett https://www.newcastle-mitochondria.com/sarah-pickett/
Professor Matthew Collin
Dr. Oliver Russell http://www.newcastle-mitochondria.com/oliver-russell/

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 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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs.
Includes:
- Stipend at national UKRI standard rate
- Tuition fees
- Research training and support grant (RTSG)
- Travel allowance

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Boggan RM, Lim A, Taylor RW, McFarland R, Pickett SJ “Resolving complexity in mitochondrial disease: Towards precision medicine” Mol Genet Metab 2019 https://doi.org/10.1016/j.ymgme.2019.09.003

Pickett SJ, Blain A*, Ng YS, Wilson IJ, Taylor RW, McFarland R, Turnbull DM, Gorman GS “Mitochondrial Donation - Which Women Could Benefit?” N Engl J Med. 2019 May 16;380(20):1971-1972.

Grady JP*, Pickett SJ, Ng YS, Alston CL, Blakely EL, Hardy SA, Feeney CL, Bright AA, Schaefer AM, Gorman GS, McNally RJQ, Taylor RW, Turnbull DM, McFarland R “mtDNA heteroplasmy level and copy number indicate disease burden in m. 3243A> G mitochondrial disease” EMBO Mol. Med. 2018, 10(6):e8262

How good is research at Newcastle University in Psychology, Psychiatry and Neuroscience?

FTE Category A staff submitted: 51.58

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