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MRC DiMeN Doctoral Training Partnership: Personalised mitochondrial health: a functional and multi-omic assessment to predict individual susceptibility to hepatotoxicity of antiepileptic drugs

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  • Full or part time
    Dr Amy Chadwick
    Dr A Alfirevic
    Dr R Jenkins
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background: The realisation that mitochondrial genetics are an important, and under-researched, factor in personalised medicine is growing. This recognition prompted the establishment of a unique, integrative program at the MRC Centre for Drug Safety Science (CDSS) in 2014 in order to define the role of mitochondrial genetics in the onset of adverse drug reactions and this studentship seeks to continue and strengthen this successful research program. As such aim of this studentship is to evaluate the role of individual mitochondrial function and genetics in determining the risk of patients developing hepatotoxicity to a panel of anti-epileptic drugs (AED) associated with drug-induced liver injury (DILI). An integrated, multi-omic approach will be utilised in which functional, genomic, proteomic and metabolomic investigations are performed in tandem supported by specialised bioinformatic analysis.
Many anti-epileptic drugs (AED) are associated with adverse effects on the liver and are known to induce mitochondrial dysfunction. These encompass a range of severity from rare idiosyncratic life-threatening , such as hepatotoxicity associated with sodium valproate which can cause acute liver failure in a small-number of patients, to transient, elevations in liver ALT levels, encountered by many patients taking drugs such as carbamazepine. Understanding more clearly the genetic and mechanistic factors predisposing to these adverse effects and their severity will inform the safer, targeted use of these drugs.
Project description: This approach requires the use of an advanced in vitro model; a panel of liver-specific transmitochondrial cybrids. Essentially in this method we can replace the mitochondrial DNA (mtDNA) of a standard laboratory model cell (HepG2) with mtDNA from volunteers or patients using their platelets as the mtDNA donor, thus allowing the reproducible examination of the effects of individual mtDNA against a constant nuclear background. The cybrids will be utilised to elucidate the molecular and chemical pathways linking mitochondrial dysfunction and cell death and furthermore to investigate the effect of mitochondrial genetic and epigenetic variation on sensitivity to AEDs. Finally, quantitative metabolomic and proteomic investigations will seek to identify potential biomarkers of susceptibility or toxicity.

Research Training and Supervision: This studentship would provide a unique training opportunity to be trained both in bioinformatic/molecular genetic investigation and the functional assessment of the role of genetics using in vitro models by a highly experienced supervisory team each with complementary research skills. The student would receive training from the primary supervisor Dr Amy Chadwick (https://www.liverpool.ac.uk/translational-medicine/staff/amy-chadwick/) in fundamental molecular toxicology at the CDSS. This would include advanced cell culture, molecular biology and the functional assessment of mitochondrial activity and dysfunction. The student will receive training at the Wolfson Centre for Personalised Medicine, a world renowned centre of excellence for pharmacogenetics research, with the secondary supervisor Dr Ana Alfirevic. Specifically, this training would include mitochondrial genome sequencing methodology bioinformatics, statistical genetics, medium to high throughput genotyping, multi-omic data integration and biobanking. Most importantly, in addition to these molecular genetics, bioinformatics and pharmacogenetic skills. Further training in quantitative proteomic and metabolomic analysis and pathway analysis would be provided by Dr Roz Jenkins (https://www.liverpool.ac.uk/translational-medicine/staff/rosalind-jenkins/).

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 2019.

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: https://goo.gl/8YfJf8
Good luck.

References

Alfirevic A & Pirmohamed M. Genomics of Adverse Drug Reactions. Trends in Pharmacological Sciences (2017) 38:100.

Ball A, Kamalian L, Alfirevic A, Lyon J, Chadwick A. Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells. Toxicological Sciences (2016) 153:341

Carr D, Alfirevic A, Johnson R, Chinoy H, van Staa T, Pirmohamed M. GATM gene variants and statin myopathy risk. Nature (2014) 513:7518



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