MRC DiMeN Doctoral Training Partnership: Identification of accessible biomarkers reflecting drug stimulation of the NRF2 antioxidant pathway in humans

Description

The transcription factor NRF2 protects cells from oxidative stress and inflammation. It plays a significant role in various diseases (e.g. cancer, neurodegeneration, metabolic disorders) and is a promising target for new therapies. There are already two classes of NRF2 activating drugs approved for clinical use, with more in development across the pharmaceutical industry. However, these drugs often target other molecules besides NRF2, and there is no accepted, non-invasive method to measure NRF2 activity in humans, such as using blood samples. This lack of biomarkers is a significant barrier to understanding if drugs targeting NRF2 are working as intended, and to fully appreciating their benefits and risks. This PhD project builds on our recent work with the goal of identifying accessible biomarkers that are indicative of NRF2 pathway activity, making it possible to monitor the effectiveness of NRF2-targeting drugs in patients. These biomarkers might include proteins released from tissues stimulated by drugs, or genes/proteins in circulating blood cells directly affected by the drugs.

The project will integrate laboratory and computational methods (anticipated split 75:25) to identify the most promising accessible biomarkers of NRF2 activity, with work sub-divided into the chapters of the PhD thesis (all necessary ethical approvals are in place):

1.     Use of computational tools and public ‘omics data sets to establish an ‘NRF2 activity score’ that can quantify the response to drug stimulation in humans.

2.     Testing of the ‘NRF2 activity score’ in perfused human liver tissue following treatment with NRF2 activating drugs.

3.     Identification of proteins secreted from human liver tissue in response to NRF2 activating drugs.

4.     Transcriptomics analysis of human blood to further test the ‘NRF2 activity score’ and identify the cell types most responsive to NRF2 activating drugs. 

You will be based at the Centre for Drug Safety Science at the University of Liverpool, under the primary supervision of Professor Ian Copple (links: website and X). The group has £3M of active research funding and currently comprises 4 PhD students, 3 post-doctoral researchers and 1 technician from diverse backgrounds. To support early progress, you will be partnered with an experienced post-doc for day-to-day guidance in mastering new techniques and planning experiments. As your confidence and skills develop, you will be empowered to take ownership of your project, with progress monitored through regular meetings with the supervisory team. The secondary supervisor, Professor Andy Jones (links: website and X), is Director of the Computational Biology Facility in Liverpool. He brings expertise in bioinformatics and the integration of different types of ‘omics data.

The project will blend the supervisors’ expertise in wet lab and computational biology, with training provided in techniques including primary liver cell isolation, culture and drug treatment, tissue perfusion, transcriptomics and proteomics analyses, bioinformatic interrogation of large data sets, qPCR and immunoblotting. The training will support the scientific progression of the project and provide you with a rounded, transferable skill set reflecting modern trends in biomedical science. As a result, you will be well positioned for a future career in either academia or industry.

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/