Understanding the benefits and risks of the therapeutic targeting of the Nrf2 stress response

Description

This studentship is fully funded for 4 years and is due to start in October 2024. Important: the tuition fee element of the studentship covers the fee rate for UK students only. See funding notes below for further details.

The transcription factor Nrf2 coordinates the cellular response to oxidative stress and is an attractive therapeutic target in several disease areas, including neurodegeneration, metabolic disorders and cancer. Most drugs that stimulate this pathway work by disrupting the ability of the redox sensor protein Keap1 to repress Nrf2. To date, two such Nrf2 activators have been approved for clinical use, yet both require long-term monitoring of patients for potential toxicities. Several pharmaceutical companies are developing alternative Nrf2 activators with different modes of action, including small molecules and RNA-based therapies. The aim of this PhD studentship is to gain a deeper understanding of the benefits and risks of targeting Nrf2 using these different modalities. This will support the ongoing development of novel medicines in a range of disease areas.

The project will be divided into three segments, representing the chapters of the PhD thesis. This will include: (1) Determining the relationship between efficacy (Nrf2 activation) and safety (cell death) for a range of Nrf2 activators with different modes of action; (2) Using a combination of proteomics and genetic interference to determine the toxicological relevance of the disruption of Keap1 binding partners by Nrf2 activating drugs; (3) Investigating the mechanism and species specificity of the liver toxicity of Nrf2 activating drugs using cryopreserved primary hepatocytes and multi-cell spheroids.

You will be based at the Centre for Drug Safety Science at the University of Liverpool, under the supervision of Professor Ian Copple (links: website and Twitter). The PhD project is aligned with a Senior Fellowship (2023-2028) awarded by the Medical Research Council to Professor Copple, to tackle key translational knowledge gaps that could impede the therapeutic targeting of Nrf2 in certain clinical contexts. The group currently comprises 3 PhD students and 3 post-doctoral researchers. We work with several industry partners that are developing Nrf2 activating drugs, and there is potential to work alongside these partners in the PhD project. In addition to his work on Nrf2, Professor Copple also leads the Human Liver Research Facility (link: website), which offers expertise in the isolation, cryopreservation and culture of primary human liver cells derived from tissue donated by patients undergoing surgery at the Royal Liverpool Hospital, situated over the road from the University. See the references below for examples of our expertise in these areas.

Training will be provided in techniques including primary liver cell isolation, culture and drug treatment, ‘omics and bioinformatics analyses, 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.

Applicants should have (or be expected to obtain) at least an upper second class (2:i) degree in a relevant subject at undergraduate level, and ideally a Masters level degree with relevant laboratory training.

Informal enquiries/discussion with Professor Ian Copple are encouraged prior to submitting a formal application.

Interviews are anticipated to take place in May 2024