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To assess how the mitochondrial tRNAome responds to Toxic Injury and reprogrammes mitochondrial translation


   Medical Research Council Toxicology Unit

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  Prof A Willis  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Disruption of mitochondrial function is a common cause of adverse drug reactions (ADR) and mitochondrial toxicity is thought to be responsible for up to 50% of post-market drug withdrawals. Mitochondrial toxins often have a differential effect on tissue function. For example, cardiomyocytes are particularly sensitive to mitochondrial toxins that alter ATP production. Many drugs that have an "off target" effect on the mitochondria target the electron transport chain ETC (see e.g Stephenson et al 2020) and 13 mRNAs that encode components of the ETC are translated on mitoribosomes, requiring mitochondrial tRNAs for their decoding.  Overall, there are 22 mitochondrial tRNAs, which are highly modified, and their importance in normal cellular homeostasis is exemplified by the large numbers of mutations in mitochondrial tRNAs (and changes in their modification status) that are associated with a range of life-limiting human diseases. There is evidence to demonstrate that cytoplasmic tRNAs vary significantly between tissues, cell types, disease states and in response to toxic injury. However, the response of the mitochondrial tRNAome to mitochondrial toxins has not been studied. The overall aim of this project is to determine how the mitochondrial tRNAome is rewired upon exposure to a range of therapeutic agents, including anti-cancer chemotherapeutics, to gain a detailed mechanistic understanding of this response.

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).

Students are registered for their PhD with the Graduate School of Life Sciences at the University of Cambridge and have membership of a University of Cambridge College. 

The ideal candidate will have excellent academic abilities (a good 2.1 honours degree or equivalent undergraduate degree) combined with strong communication and team working skills in order to make the most of interdisciplinary training opportunities.

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


Funding Notes

This is a four year PhD project and comes with funding for tuition fees (at Home rate) and a maintenance stipend of £17,500 per annum.
To be eligible for full funding candidates will need to demonstrate that they have Home fee status.
Candidates of any nationality/residency can also apply and will be considered for a fees-only (at Home rate) award. Candidates would therefore need to secure additional funds from other sources to cover the higher tuition fee and their maintenance stipend. The most current estimates of costs can be found on the Graduate Admissions fees page.

References

Zoe A Stephenson.. et al Anne E Willis (2020) Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I eLife.9: e55845. doi: 10.7554/eLife.55845. PMCID: PMC7316505
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