MRC DiMeN Doctoral Training Partnership: Cracking the Mitochondrial Code: New Frontiers in Tackling Linezolid Toxicity for Multi-Drug Resistant Tuberculosis

We invite applications for a fully funded PhD studentship to explore the role of mitochondrial DNA (mtDNA) in adverse drug reactions (ADRs) to linezolid, a key drug in treating multidrug-resistant tuberculosis (MDR-TB). This research aims to improve linezolid’s safety in treating MDR-TB, a critical global health issue. Furthermore, the novel focus of this studentship on mtDNA, rather than nuclear DNA will contribute new understandings and methodology to an exciting new frontier in pharmacogenomics.

Project Overview

Linezolid is known to inhibit mitochondrial protein synthesis, and this mechanism is thought to underlie its toxic side effects. The objective of this studentship is to understand whether inter-individual variability in mtDNA plays a role in susceptibility to the ADRs associated with linezolid. This research builds on collaborations with Médecins Sans Frontières (MSF), through which you will have access to clinical samples from patients treated with linezolid. You will use this data to develop an innovative functional polygenic score, the mtDNA variant load model, to examine how mtDNA variations impact risk of linezolid-related ADRs. To add further mechanistic detail, you will combine these genomic investigations with functional validation studies, using a bespoke in vitro model for the study of mtDNA in drug safety (HepG2 transmitochondrial cybrids). This project benefits from having all clinical and genetic data collected and available, with all the necessary technology, equipment, and expertise in place.   

Scientific Skills Training

As part of this multidisciplinary project, you will develop a wide range of bioinformatic and laboratory skills, essential for conducting cutting-edge translational and functional genetic research. You will be primarily based at the University of Liverpool, working in the research labs of Dr Chadwick (www.liverpool.ac.uk/people/amy-chadwick) and Dr Carr (www.liverpool.ac.uk/people/daniel-carr). Here, you will gain hands-on experience in handling clinical samples, conducting genotyping, and mastering advanced cell culture techniques. Additionally, you will learn to perform functional toxicology assays, which are crucial for measuring mitochondrial activity, function, and cytotoxicity in relation to drug safety. Dr Joanna Elson (www.ncl.ac.uk/medical-sciences/people/profile/joannaelson.html), from Newcastle University, will provide training in analyzing and interpreting mtDNA variation. You will be guided through the development of functional polygenic scores (mtVLM), a key component of the project, and learn how to apply this knowledge to real-world pharmacogenomic studies.

Environment

You will be part of a dynamic and collaborative research environment across two leading institutions. At Liverpool, in the Dept of Pharmacology & Therapeutics, you’ll join a cutting-edge research community specializing in drug safety, toxicology, and pharmacogenomics, with access to state-of-the-art facilities and technologies. We are proud of the vibrant academic culture, featuring regular seminars, workshops, and networking opportunities including a thriving postgraduate community. Furthermore, the collaboration with Newcastle will provide you with the opportunity to build extended networks with colleagues at a world-renowned centre for mitochondrial genomics, recognized for its innovation and strong connections between bioinformatics and genetics research. All supervisors, and  both, institutions champion an environment of inclusivity, prioritising mental well-being, and a healthy work-life balance. Overall, you’ll be part of a global research network, contributing to high-impact science in a supportive environment.

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/