Use of a systems toxicology approach to understand the role of liver metabolism and stress responses in drug toxicity

Description

This studentship is fully funded for 4 years by the MRC Integrative Toxicology Training Partnership (ITTP), and is due to start in October 2023.

The safety assessment of new medicines is increasingly benefitting from new approaches to understand clinical risks based on the results of preclinical testing. This includes systems toxicology approaches, which combine mathematical/computational modelling of biological processes (e.g. genome-scale metabolic networks; GSMNs) with wet lab techniques to predict drug effects. Currently, there is a clear gap in the training of the next-generation of drug safety scientists/toxicologists in this area. Such individuals need to be comfortable with the use of both computational modelling and in vitro biological tools so that they can bridge the inter-disciplinary divide and realise the potential of a synergistic systems toxicology approach for drug development. With a focus on the liver, this project will use a systems approach to investigate the toxicological implications of inter-patient variability in the activity of the Nrf2 oxidative stress response pathway. The project will be divided into three segments, representing the chapters of the PhD thesis. This will include: (1) Experimental verification and refinement of existing metabolic network models (e.g. HepatoNet1, MitoCore); (2) Use of the modelling approach to predict and confirm the toxicological impact of inter-individual differences in Nrf2 pathway activities; (3) Use of the modelling approach to support the generation and testing of hypotheses for on/off-target safety concerns related to specific GSK compounds. There will be opportunities to spend time at GSK during the project. The outcome of the project will be a calibrated model of hepatic/mitochondrial metabolism that can be used for hypothesis testing/generation for on/off target safety liabilities during the drug development process.

You will be based at the Centre for Drug Safety Science at the University of Liverpool, under the supervision of Dr Ian Copple (links: website and Twitter), who holds a prestigious MRC Senior Fellowship in Nrf2 pharmacology/toxicology and has a long-standing interest in drug-induced liver toxicity. Dr Copple is also the academic lead of the Human Liver Research Facility, which offers expertise in the isolation, cryopreservation and culture of primary human liver cells derived from tissue donated by patients undergoing surgery at the brand new Royal Liverpool. You will also be supervised in Liverpool by Dr Tao You, who has expertise in mathematical/computational modelling, and at GSK by Dr Ciarán Fisher and Dr Jon Lyon, who are based in the Non-clinical Safety Group and have expertise in the industrial application of mathematical/computational modelling within the drug development process. See the references below for examples of our expertise in these areas.

Together, the supervisors and their group members will provide you with training in techniques including primary liver cell isolation, culture and drug treatment, computational modelling, metabolite quantification, assessment of mitochondrial function, transcriptomics analysis, qPCR and immunoblotting. You will also attend the annual ITTP Summer School hosted by the MRC Toxicology Unit in Cambridge. The training will support the scientific progression of the project and provide you with a rounded, transferable skill set reflecting modern trends in biological and computational science. As a result, you will be well positioned for a future career in either academia or industry.

Applicants should have (or be expected to obtain) at least an upper second class (2:i) degree in a Biological or Life Science subject. Given the multi-disciplinary/sector nature of this project, the ideal candidate for this studentship will have a biology/molecular biology background and a keen interest in mathematical/computational modelling. They should also have an interest in both academic research and industrial drug discovery. Please evidence these aspects in your application.

All applications to be submitted by email to Dr Ian Copple ian.copple@liverpool.ac.uk

Applications must include:

  • A CV, including full details of all University course grades to date
  • Contact details for two academic or professional referees
  • A personal statement of interest

Availability

Open to UK applicants

Funding information

Funded studentship

This studentship is fully funded for 4 years by the MRC Integrative Toxicology Training Partnership. This includes a stipend of £17,668 per year (to cover the cost of living expenses), postgraduate tuition fees (at the UK student rate) and a research budget (to be held by the supervisor). EU and international students are welcome to apply provided they can confirm at the time of application that they can cover the additional £21,354 per year required for non-UK student tuition fees. Please confirm this and the source of the additional funding in your application, otherwise it will not be considered.

Supervisors

References

Russomanno G, Sison-Young R, Livoti LA, Coghlan H, Jenkins RE, Kunnen SJ, Fisher CP, Reddyhoff D, Gardner I, Rehman AH, Fenwick SW, Jones AR, Vermeil De Conchard G, Simonin G, Bertheux H, Weaver RJ, Johnson RL, Liguori MJ, Clausznitzer D, Stevens JL, Goldring CE, Copple IM (2022) A systems approach reveals species differences in hepatic stress response capacity, bioRxiv, doi.org/10.1101/2022.04.13.488145

Huang ZH, You T (2021) Personalise dose regimen of vitamin D3 using physiologically-based pharmacokinetic modelling. CPT Pharmacometrics Syst Pharmacol. 10(7): 723-734.

Maldonado EM, Leoncikas V, Fisher CP, Moore JB, Plant NJ, Kierzek AM (2017) Integration of Genome Scale Metabolic Networks and Gene Regulation of Metabolic Enzymes With Physiologically Based Pharmacokinetics, CPT Pharmacometrics Syst Pharmacol, 6: 732-746.

Maldonado EM, Fisher CP, Mazzatti DJ, Barber AL, Tindall MJ, Plant NJ, Kierzek AM, Moore JB (2018) Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease, NPJ Systems Biology and Applications, 4: 33.