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MRC DiMeN Doctoral Training Partnership: Evaluation of the pharmacology and toxicology of next-generation Nrf2 activators; novel drugs for the treatment of diseases associated with oxidative and metabolic stress


   Faculty of Health and Life Science

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  Dr I Copple, Dr Richard Mead, Prof A Jones  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Diseases associated with aging and poor lifestyle are often underpinned by inflammation and oxidative stress. Activation of the transcription factor Nrf2 and its downstream anti-inflammatory and anti-oxidant gene network is emerging as a potential therapeutic strategy for combatting neurodegenerative diseases and metabolic disorders, amongst other indications. Until recently, therapeutic Nrf2 activation has been achieved using electrophilic agents that disable Keap1, the redox sensitive inhibitor of Nrf2. Yet such electrophiles have other protein targets, and the contribution of these residual interactions to the therapeutic effects and emerging liver safety concerns associated with Nrf2 activators is not clear.

Recently, new classes of Nrf2 activator have been developed, including small molecule inhibitors of the interaction between Nrf2 and Keap1, cell permeable peptides designed to compete for Keap1 binding, and synthetic mRNA encoding Nrf2. The aim of this project is to compare and contrast the pharmacology and toxicology of electrophilic and non-electrophilic Nrf2 activators using in vitro and in vivo approaches. The goal is to inform the ongoing development of such agents as novel therapeutics in a range of disease areas.

The project will be divided into four segments, representing the chapters of the PhD thesis. This will include: (1) The use of luciferase reporter cell lines to determine the relationship between efficacy and safety for a series of electrophilic and non-electrophilic Nrf2 activators; (2) Transcriptomics and bioinformatics -based investigation of the different networks of genes influenced by these forms of Nrf2 activation in cells; (3) Comparison of the therapeutic potential of electrophilic and non-electrophilic Nrf2 activators in the context of amyotrophic lateral sclerosis (ALS) using a primary astrocyte toxicity assay; (4) Assessment of the liver toxicity risk associated with electrophilic and non-electrophilic Nrf2 activators.

You will be based at the Centre for Drug Safety Science at the University of Liverpool, under the supervision of Dr Ian Copple (links: website and Twitter) and Prof Andy Jones (links: website and Twitter). You will also spend some time working with Dr Richard Mead (links: website and Twitter) at the University of Sheffield. Dr Copple holds a prestigious MRC Senior Fellowship in Nrf2 pharmacology/toxicology, Prof Jones leads the Liverpool Computational Biology Facility, and Dr Mead is co-founder and Chief Scientific Officer of Keapstone Therapeutics, who are developing Nrf2 activators for the treatment of neurodegenerative diseases. See the references below for examples of our expertise in these areas. All of the supervisors have well-funded research groups with several post-docs and PhD students. Together, the supervisors and their group members will provide you with training in 2D/3D culture of cell lines and primary cells, transcriptomics analysis, computational bioinformatics, in vivo skills and the integrated assessment of liver toxicity. The training will support the scientific progression of the project and provide you with a rounded, transferable skill set reflecting modern trends in biological 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, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

Chan et al. (2021) Pharmacological activation of Nrf2 enhances functional liver regeneration, Hepatology, 74(2), 973-986. https://pubmed.ncbi.nlm.nih.gov/33872408/
Jiménez-Villegas et al. (2021) NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS, Free Radical Biology & Medicine, 173, 125-141. https://pubmed.ncbi.nlm.nih.gov/34314817/
Wang et al. (2022) Integrated view and comparative analysis of baseline protein expression in mouse and rat tissues, PLoS Computational Biology, 18(6), e1010174. https://pubmed.ncbi.nlm.nih.gov/35714157/
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