Using patient-derived iPS cells to understand molecular mechanisms underpinning variation in patient susceptibility to mitochondrial insult and drug-induced toxicity

Supervisors: Prof. Marion MacFarlane (MRC) & Dr. Stefan Kavanagh (AZ)

The Medical Research Council Toxicology Unit is an internationally renowned institution focussed on the delivery of field-changing mechanistic insights into toxicology and disease. The Unit is equipped with state-of-the-art facilities and provides a supportive learning environment designed to meet the scientific and transferable skills required for an internationally competitive career.

The Toxicology Unit will be relocating to the University of Cambridge in 2020.

This MRC studentship, in collaboration with AstraZeneca (AZ) R&D Cambridge, is for 3.5 years commencing September/October 2017 with an annual stipend of £15,000 (tax free).

Background:
During the drug discovery phase, safety assessment spend a considerable amount of time and resource attempting to characterise and mitigate risks that might only manifest in a relatively small proportion of patients (<1%). Differences in patient mitochondrial capacity may contribute to these differences in Adverse Drug Reactions (ADR) in patients, whether it be mitochondrial oxygen consumption rate, mitochondrial mass or speed/ability of mitochondria to respond to stress. This studentship aims to utilise patient-derived induced-Pluripotent Stem (iPS) cells to identify the molecular mechanisms responsible for variations in mitochondrial susceptibility. The differences identified would then be used to select a battery of cardiomyocyte and hepatocyte culture models, which recapitulate patient variability using training compounds with known mitochondrial liabilities. This would enable the development of mitochondrial-targeted screening of patient-specific phenotypes during the drug design phase. If successful, this approach will enable discovery projects to ‘design out’ compounds with a high potential risk of mitochondrial liability as well as identify biomarkers that could be used to screen patients at risk of mitochondrial ADR, thereby allowing for better informed risk assessment/clinical monitoring.

Training Objectives
This project represents an ideal opportunity to learn a range of state-of-the-art techniques including, profiling of mitochondrial mass/function, 3D visualization of mitochondrial structure, FACS analysis, bioinformatics & human iPS cell culture.

The University of Leicester runs a variety of training modules and courses which student are encouraged to attend. In addition, the student will follow the Toxicology Unit’s weekly external and internal seminar programs and be included in the postdoc/student forums which take place each month and offer excellent opportunities for collaboration and career development.