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  Determining the role of mitochondrial DNA variation in hepatic pathways and its impact on physiology, pharmacology and toxicology: a combined in vitro and bioinformatic approach.


   Department of Pharmacology and Therapeutics

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  Dr Amy Chadwick, Dr Dan Carr, Dr Joanna Elson  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Project Background and Aims: It is widely known that differences in the nuclear genome contribute to aspects of us as individuals, from hair colour to lifespan. However, less well-known is that we all have a second source of DNA called mitochondrial DNA (mtDNA). mtDNA is only inherited from our mothers and is much smaller, coding only 13 genes involved in producing cellular energy . However, research has shown that changes in mtDNA can have profound effects not only on how we produce energy but also in phenotypic responses to ageing, disease and organ function.

Research has begun to identify nuclear DNA factors that have a critical role in hepatic function, but the potential role of mtDNA variation has not been considered. In part, this is due to two major limitations. Firstly, it has not been possible to study the effect of mitochondrial variation against a common nuclear background. Secondly, most population studies are grossly underpowered when considering mitochondrial variation. In this studentship, you will circumvent these longstanding limitations using an innovative approach. Specifically, your project will combine a novel cell-based technology, in the form of an in vitro model that enables the effects of distinct mitochondrial genotypes to be studied against a constant nuclear background. You will also learn how to calculate and apply a polygenic risk score specifically for mtDNA, called the mtDNA variant load model (mtVLM). Critically this project will be used to further develop this model. Thus, you will gain skills in two trending domains of current research, bioinformatics and genetic modelling alongside utilising molecular biology to define fundamental mechanisms

It is the overall aim of this studentship to define hepatic pathways that are under the influence of mtDNA, to explore the impact of any cross-talk between the nuclear and mitochondrial genomes and to identify potential genetic associations. To do this you will use hepatic transmitochondrial cybrids. This research in this studentship will provide a novel understanding of this overlooked, potential regulatory, axis with likely implications for understanding an individual’s susceptibility to liver disease as well as its subsequent treatment.

Student Experience: In this project, the student receive training across a diverse range of computational and laboratory skills with which to undertake pioneering translational, functional genetic studies. They will be trained to use cutting-edge technology and complex data analysis, with advanced systems biology to build the mtVLM computational model.

The successful student will be trained in techniques including advanced cell biology transmitochondrial cybrid generation, molecular biology, proteomics, lipidomics and a suite of functional analyses. This rich dataset will then be used as the source for subsequent computational studies to develop and validate the mtVLM to reveal the potential regulatory role of the mitochondrial genome upon hepatic function.

Research Environment: The student will be embedded across two world-leading research institutes within the laboratories of their supervisors. They will spend their first 12 months at the host institute (Dept of Pharmacology & Therapeutics, University of Liverpool, Dr Amy Chadwick & Dr Dan Carr) to generate the in vitro models and to begin data collection. At the start of year 2, they will spend 3 months at the Wellcome Centre for Mitochondria Research (Newcastle University, Dr Joanna Elson). Here, they will be introduced to computational modelling and methodology which they will continue to work on whilst they are back at the host institution in years 2 and 3.

Applicant Information: The successful applicant should have an interest in basic biomedical and bioinformatics research and hold a minimum undergraduate qualification 2:1, or equivalent, in a life science or health-related subject.

Research project related enquiries should be made in the first instance to Amy Chadwick ([Email Address Removed]).

To apply please send your CV and a covering letter to Dr Amy Chadwick ([Email Address Removed]).


Biological Sciences (4) Mathematics (25) Medicine (26)

Funding Notes

We are looking for a self-funded students who has secured funding from an independent body. There is no financial support available from Liverpool for this study. Please see website for PhD student fees at the University of Liverpool https://www.liverpool.ac.uk/study/postgraduate-research/fees-and-funding/fees-and-costs/.
The successful applicant will be expected to have funding in place for the tuition fees (check University of Liverpool website), consumables/bench fee (£ 16000 per annum) and living expenses during their stay in Liverpool.

References

The generation of HepG2 transmitochondrial cybrids to reveal the role of mitochondrial genotype in idiosyncratic drug-induced liver injury: a translational in vitro study (2022) bioRxiv 2022.03.21.485109; doi: https://doi.org/10.1101/2022.03.21.485109
Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers. (2021) Arch Toxicol 95,1335–1347
Investigation of the correlation between mildly deleterious mtDNA Variations and the clinical progression of multiple sclerosis. (2021) Mult Scler Relat Disord. 53:103055.
Heterologous Inferential Analysis (HIA) and Other Emerging Concepts: In Understanding Mitochondrial Variation In Pathogenesis: There is no More Low-Hanging Fruit. (2021) Mitochondrial Medicine; 2277:203-245.

Where will I study?

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