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(BBSRC NWD CASE) Probing the role of non-canonical NRF2-Retinoic acid signalling cross-talk in neuromuscular ageing using novel synthetic retinoids and chronobiology approaches

Funding
Funded
Study mode
Full-time
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Start date
Subject area
Biological and Biomedical Sciences
How to apply
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Overview

In this exciting PhD project, the student will be trained in a broad context of neuromuscular ageing, circadian physiology, pharmacogenetics, big data science and in silico modelling. The student will utilise a range of interdisciplinary 'state-of the art' techniques to perform cutting-edge research (e.g. real-time bioluminescence imaging, omics profiling, ChiPseq) established by supervisors from two academic institutions (Universities of Liverpool/Manchester) and an industrial partner (Nevrargenics).

About this opportunity

iCASE industrial partner web link: https://nevrargenics.com/

Ageing is characterized by a loss of neuromuscular system function and muscle mass/strength, which contributes to frailty and lower quality of life. NRF2-mediated redox signalling has emerged as an important regulator of neuromuscular homeostasis/regeneration. Most of its effects are mediated by NRF2/sMAF co-factor binding to ARE-responsive elements to positively regulate target antioxidant genes. However, recent work in our laboratory and those of others have revealed that NRF2 can act through non-canonical pathways by partnering with other transcription factors to perform a role as a transcriptional repressor. Indeed, our recent transcriptomic profiling data from mouse tissues has revealed that under various environmental cues (e.g. cold adaptation, mechanical loading), NRF2 can negatively regulate a broad set of transcriptional programmes from glycolysis, lipid storage and mitochondrial metabolism to immune responses and longevity pathways. However, how NRF2 cooperates with other transcriptional partners (e.g. retinoic acid receptors -RARs- mediating retinoic acid (RA) signalling) to exert a repressor role in skeletal muscle maintenance and regeneration during ageing is completely unknown.

We have previously demonstrated that NRF2-redox pathway and its genetic or pharmacological activation is subject to circadian clock regulation. Moreover, our recent preliminary data uncovered a bi-directional feedback loop between the skeletal muscle clock and the RA signalling. Circadian timing regulates many physiological processes in the body, and is an important determinant of drug success-it modifies up the extent of tolerability and doubles the extent of efficacy of many drugs. In this exciting PhD project, in collaboration with industrial partner, who has developed a panel of novel dual-acting synthetic retinoid agonosts (with improved potency and increased light stability), the PhD student will probe the non-canonical role of NRF2/RA signalling in skeletal muscle maintenance and ageing, which has a potential to discover novel therapeutic targets for slowing down the rate of neuromuscular decline with ageing.

The project will investigate three major aims encompassing following hypotheses that:

  1. Ageing of skeletal muscle tissues and muscle progenitor cells leads to altered circadian regulation of NRF2/RA signalling and its targets,
  2. Genetic loss of Nrf2 or RA signalling in skeletal muscle mimics age-related changes in NRF2/RA targets and downstream metabolic pathways, and
  3. Skeletal muscle changes with age can be partially rescued using time-of-day targeting with novel synthetic retinoids.

Further reading

1. A combination of major histocompatibility complex (MHC) I overexpression and type I interferon induce mitochondrial dysfunction in human skeletal myoblasts. J Cell Physiol. 2024:e31458.
2. Nrf2/AMPK axis is required for redox-mediated phase resetting of musculoskeletal clocks upon acute mechanical loading. Free Radical Biology and Medicine doi:10.1016/j.freeradbiomed.2025.05.266.
3. Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis. Redox Biol. 2024 69:102980.
4. Adipocyte NR1D1 dictates adipose tissue expansion during obesity. Elife. 2021 10:e63324.
5. Introduction to MATLAB® for Biologists. Springer International Publishing. 2020 doi:10.1007/978-3-030-21337-4

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Who is this for?

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

International applicants

We are only able to offer a limited number of full studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality international candidates due to the competitive nature of this scheme.

International applicants must ensure they meet the academic eligibility criteria (including English language) before applying. Visit our English Language requirements page to find out more.

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How to apply

  1. 1. Contact supervisors

    The PhD project will include two rotations; one with UoM co-supervisors, with expertise in circadian metabolic pathways and in vivo transgenic approaches. During the second placement with an industrial partner, in addition to pharmacological drug assays, the student will gain invaluable insights into the process of commercialising scientific research, generating intellectual property and patents.

    Supervisory team:

    For any queries, please email the primary supervisor, Dr Vanja Pekovic-Vaughan, in the first instance 

  2. 2. Prepare your application documents

    Browse our BBSRC NWD in Bioscience projects and discover one you’re passionate about that matches your interests, ambitions and goals.

    Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

    How to Apply

    All applications should be submitted through the University of Manchester application portal.

    Apply directly via this link, and select BBSRC DTP PhD as the programme of study. You may apply for up to two projects from the programme via this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.

    Please ensure that your application includes all required supporting documents:

    • Curriculum Vitae (CV)
    • Supporting Statement
    • Academic Certificates and Transcripts

    Incomplete or late applications will not be considered.

    Applications should not be made through the University of Liverpool’s application portal.

    You must submit your application form along with the required supporting documents by the deadline date. You can select up to two projects on one single application, noting the title of each project from the advert and the supervisor name. This can include two projects from one institution or a project from each institution.

    Once you have completed your application, you’ll receive a confirmation email.

    Deadline: Sunday 7th December, midnight (UK time)

    Late or incomplete applications will not be considered.

    If you need help with this stage of the process, or have any queries regarding your eligibility (such as if you achieved unexpectedly low degree results due to extenuating circumstances), please contact the Liverpool BBSRC team for advice at 

  3. 3. Apply

    Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.

    Once you have applied through the University of Manchester portal, and if you are successfully offered a studentship following a formal interview, you will be instructed to apply formally through the University of Liverpool. You must only do this once you have been instructed to do so.

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Funding your PhD

This is a 4 year CASE studentship in partnership with Nevrargenics available to UK and international applicants, and provide funding for tuition fees and stipend at the UKRI rate, subject to eligibility, for four years.. This covers tuition fees and an annual stipend. This does not include any costs associated with relocation.

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Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.

Liverpool BBSRC team
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