Mitochondrial Toxicity in Idiosyncratic Drug-induced Liver Injury (iDILI): defining contribution and mechanisms in monocyte-derived hepatocyte-like (MH) cells from iDILI patients for safer drug development

This is a fully funded 4-year MRC Integrative Toxicology Training Partnership (ITTP) PhD Studentship, commencing on 1st October 2023.

In drug development, Drug-induced liver injury (DILI) is a serious ADR, and a common driver of drug attrition in phase I-III trials across therapeutic areas (Weaver et al. 2021). Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnosis in clinic & drug development because its occurrence is determined by individual patient characteristics, such as genetics and environmental factors. The incidence of iDILI is rare (e.g. 1 in 10,000), but it can have potentially severe consequences: acute liver failure with the risk of death or liver transplantation.

In this project, we will build on our initial evaluation in collaboration with AstraZeneca of idiosyncratic DILI patient-derived MetaHep cells as a pre-clinical model to enable better understanding of the role of mitochondrial toxicity in iDILI. We will expand on our recent sequencing of mtDNA from iDILI patient-derived MetaHep cells which shows the potential importance of individual mitochondrial genotype in determining susceptibility to drug-induced toxicity. Our overarching hypothesis is that mitochondrial iDILI is a major driver of iDILI with inter-individual variation in mtDNA an important factor underlying mitochondrial iDILI. The student will focus on a subset of drugs known to induce iDILI (e.g. Diclofenac) to evaluate mitotoxicity in a unique set of iDILI patient-derived MetaHep cells. Using a suite of cellular and cell-free biochemical assays, they will then explore the molecular mechanisms underlying mitochondrial toxicity. To confirm the propensity of particular patients to mitochondrial toxicity, the glucose-to-galactose metabolic shift model will be employed and analysis of cell death, mitochondrial dynamics and ultrastructure, cellular bioenergetics and respiratory chain function combined with detailed analysis of mtDNA variation (Penman et al. 2020).

The project will provide the student with training in a wide range of wet lab techniques and a unique opportunity to integrate experimental laboratory skills with medicines drug safety.

The successful candidate will be jointly supervised by Prof. MacFarlane, MRC Toxicology Unit, University of Cambridge, Dr Williams at AstraZeneca, located on the Cambridge Biomedical Campus and Dr. Chadwick at the University of Liverpool.

The Medical Research Council (MRC) Toxicology Unit is a leading International Research Institute within the School of Biological Sciences, University of Cambridge. The Unit delivers mechanistic toxicology research, pursuing hypothesis-driven toxicological questions with a particular focus on the study of the causal links between exposure to endogenous and exogenous toxicants, molecular initiating events and adverse outcome pathways. The Unit's overall aims are to carry out pioneering research which leads to improved health and to train and mentor the next generation of toxicologists.

The Unit provides a supportive learning environment designed to meet the scientific and transferable skills required for an internationally competitive career. Our PhD Programme aims to train the scientific leaders of the future, giving them rewarding research projects with access to world-class facilities and expertise. Students receive toxicology-specific training in the Unit and through the Integrated Toxicology Training Partnership (ITTP).

Applicants should hold or be about to achieve a First or good Upper-Second (2.i) class degree in a relevant subject. 

To apply please visit the Toxicology Unit website and follow the instructions provided: Applications | MRC Toxicology Unit (cam.ac.uk)

You are strongly recommended to contact the project supervisor prior to submitting your formal application to find out more about the project and eligibility: [Email Address Removed]

Closing date: Friday 31^st March 2023 or until a suitable candidate is found. Early applications are recommended.