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Evaluation of the therapeutic potential of pharmacological NRF2 activation in hepatic fibrosis

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  • Full or part time
    Prof A Dinkova-Kostova
    Dr L de la Vega
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

This project is one of 16 four year PhD Studentships funded by Medical Research Scotland (https://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and External Partner Organisation (EPO). The Studentship will provide the first-class academic and additional training provided by the EPO needed to equip the successful candidate for a science career in an increasingly competitive market.

"Evaluation of the therapeutic potential of pharmacological NRF2 activation in hepatic fibrosis" to be delivered by the University of Dundee [Supervisors: Professor Albena T Dinkova-Kostova and Dr Laureano de la Vega (Division of Cellular Medicine, School of Medicine)] and Reata Pharmaceuticals, Inc (https://www.reatapharma.com/) [Company supervisor: Dr Chris Wigley].

There are no drugs to treat liver fibrosis, which at its advanced stage, leads to cirrhosis. During liver injury, oxidative stress and inflammation ensue, and a specific type of cells termed hepatic stellate cells (HSCs), are activated. Activated HSCs are responsible for liver scarring, and thus represent an attractive therapeutic target. Transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2, gene name NFE2L2) orchestrates a comprehensive transcriptional programme that protects against oxidants and inflammatory agents. NRF2-inducing compounds such as the cyanoenone triterpenoids, the most potent NRF2 activators know to date, are currently in clinical trials for various disease indications. Thus NRF2 activation represents an attractive therapeutic strategy given that a number of NRF2 activators have well-documented safety profiles in humans.

The overall goal of the proposed project is to test the hypothesis that pharmacological NRF2 activation in HSCs will circumvent oxidative stress and inflammation, thereby inhibiting fibrogenesis. First, we will test the ability of pharmacological activation of NRF2 to prevent quiescent HSC activation in response to pro-fibrogenic stimuli. Second, we will examine the ability of NRF2 activators to reverse activated HSCs to their quiescent state. Third, we will determine the anti-fibrogenic potential of a selected NRF2 activator in a 3D multi-culture liver fibrosis model. Together, these experiments will establish whether NRF2 activators hold promise for anti-fibrotic therapy in liver disease.

ENQUIRIES:
Enquiries should be sent by email to Professor Albena Dinkova-Kostova:
[Email Address Removed]

APPLICATIONS:
Applicants must have obtained, or expect to obtain, a first or 2.1 UK honours degree, or equivalent for degrees obtained outside the UK, in a relevant biological or biomedical sciences subject. Excellent oral and written communication skills are essential, as is statistical literacy and a genuine passion for research.

Applicants should send a CV, the contact details of 2 referees (including email addresses) and a covering letter, explaining why the applicant wishes to carry out this project, by email to Professor Albena Dinkova-Kostova:
[Email Address Removed]

Please note, your application may be shared with the funders of this PhD Studentship, Medical Research Scotland and Reata Pharmaceuticals, Inc.

Interviews are expected to take place 3-4 weeks after the closing date for applications. In light of the current coronavirus situation, interviews may be conducted by video conference.

It is anticipated that the PhD Studentship will start in October 2020.

Funding Notes

PhD Studentship provides: an annual tax-free stipend of £17,500, increasing to £18,000 over the four years; tuition fees at UK/EU rates only; consumables; and generous travel allowance. International fees are not covered.

References

Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, Attucks OC, Franklin S, Levonen AL, Kensler TW, Dinkova-Kostova AT. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews: Drug Discovery 2019; 18: 295-317
Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nature Reviews: Gastroenterology Hepatology 2017; 14: 397-41



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