Applications are invited for a PhD studentship at The MRC Centre of Drug Safety Science, Institute of Translational Medicine, University of Liverpool UK. The studentship is funded by the BBSRC in a Collaborative Training Partnership with AstraZeneca.
Non-alcoholic fatty liver disease (NAFLD) is a term that is used to describe several conditions where there is fat build up in the liver. NAFLD is a worldwide health concern, with estimates that it affects up to 24 % of the population, and 1 in 3 people in the UK are believed to have the early stages of fat build up in the liver. It is also known that drugs can interfere with fatty acid oxidation and mitochondrial function resulting in steatosis of the liver which can cause idiosyncratic hepatotoxicity for example, sodium valproate, amiodarone and NRTIs. However, in each case the factors underlying individual susceptibility remain unclear. The onset of fatty liver and its progression from simple fatty liver build up, steatosis, to more serious forms of NAFLD, including steatohepatitis, fibrosis and cirrhosis, has complex molecular origins. Importantly, it is evident that individual factors are important in predisposition to and severity of fatty liver. Energy metabolism, and in particular mitochondria respiration, are key processes in the build-up of fatty liver deposits as the site of fatty acid oxidation.
Personal mitochondrial function is determined by a combination of nuclear and mitochondrial genetics with external effects of lifestyle and disease. Mitochondrial DNA (mtDNA) is a key contributor to overall bioenergetic phenotype. MtDNA is inherited maternally and specific groups of polymorphisms give rise to mitochondrial haplogroups, which form the basis of mitochondrial genotype. It is known that each haplogroup can give rise to functional differences in mitochondrial activity and energy metabolism. Research has highlighted that mitochondrial genotype can impact on hepatic energy metabolism, in particular dysregulation of fatty acid oxidation
Project Description: The overall aim of this studentship is to investigate the singular effect of mitochondrial genotype upon cellular metabolism with respect to basal and aberrant fatty acid metabolism, in particular the onset of steatosis and hepatotoxicity. This approach will require the use of an advanced in vitro model; a panel of liver-specific transmitochondrial cybrids. Essentially in this model the mitochondrial DNA (mtDNA) of a standard laboratory cell (HepG2) is replaced 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 used to define the effect of mitochondrial haplogroup on energy metabolism pathways and the development of steatosis as well as the underlying molecular mechanisms. Further investigation will examine the effect of fatty acid oxidation dysregulation and lipid accumulation upon susceptibility to mitochondrial toxins.
Research Training and Supervision: The supervisors at UoL will be Dr Amy Chadwick and Dr Ana Alfirevic and the supervisor at AstraZeneca will be Dr Dominic Williams. . The student will benefit from the collaboration by gaining significant experience in an industrial research pharmaceutical setting.
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. 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 cybrid generation, molecular biology, fluorescent microscopy 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.
Requirements: Candidates should have or expect to obtain a BSc/MSc degree (2.1 or above) in a relevant biomedical or life sciences subject. Candidates are preferred with previous laboratory experience in cell/molecular biology and a strong interest in drug safety science.
English Language Requirement for EU Students is an IELTS score of 6.5 with no band score lower than 5.5.
To apply please send a Curriculum Vitae and covering letter to [email protected]
For application enquires please contact Dr Amy Chadwick ([email protected]