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The role of circadian rhythms and redox signalling in musculoskeletal stem cell ageing

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  • Full or part time
    Dr Vanja Pekovic-Vaughan
    Dr D Young
    Dr R Barrett-Jolley
    Dr A Vasilaki
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Skeletal muscle stem cell function is essential for tissue regeneration in response to injury and disease, which significantly declines with ageing. To be able to effectively use stem cell therapies to combat age-related tissue degeneration, it is important to understand the critical determinants of stem cell regulation. One such determinant is related to timing cues within the tissue microenvironment, which stem cells can sense and direct their differentiation through altering their downstream gene expression. Recent work has demonstrated the role for circadian rhythms in regulating adult stem cell responses to external cues from the microenvironment.

Circadian (24h) rhythms are evolutionary conserved timing mechanisms that keep our tissue physiology in tune with the external environment and their disruption (as a result of ageing, genetic variation, or shift work) is associated with age-related tissue dysfunction and disease. Emerging data has shown that many timed environmental stimuli, such as light, exercise and nutrients, can reset circadian clocks via redox mechanisms, suggesting an important role for feedback interactions between clocks and redox properties of the cellular niche in stem cell regulation. However, how these redox-transduction processes couple with cellular clock machinery to optimally direct skeletal muscle stem cell behaviour is currently not known.

We have previously published that NRF2-mediated redox signalling is subject to circadian regulation. Our recent data has discovered a non-canonical role for NRF2 in regulating clock genes in skeletal muscle cells and tissues. This project will investigate the following hypotheses that: 1) skeletal muscle stem cells show altered circadian regulation of NRF2 and its target miRNAs with age and 2) Nrf2 loss in skeletal muscle mimics age-related clock::miRNA changes and 3) muscle clock changes with age can be partially rescued using NRF2 target miRNA mimetics. This project will use a wide range of cross-disciplinary and ’state-of the art’ techniques in order to perform cutting-edge bioscience research. Lentiviral delivery of clock gene::luciferase reporters and real-time bioluminescent imaging will be used to track cellular clock gene rhythms. To investigate miRNA expression, a number of miRNA tools will be used including miRNA mimetics to perform microRNA gain- and loss-of-function approaches. Mathematical modelling of mechanical pathways will enable us to model key clock-controlled proteins involved in integrating spatial and timing cues that control stem cell function.

The supervisory team will bring together experts in circadian rhythms, skeletal muscle stem cells, epigenetic regulation and mathematical modelling to provide exciting laboratory and cross-disciplinary training. This will include supervisors based at the University of Liverpool (Dr Vanja Pekovic-Vaughan - primary supervisor; Prof Richard Barrett-Jolley, Dr Aphrodite Vasilaki, Dr Mirela Domijan) and Newcastle University (Prof David Young, Dr Daryl Shanley), where the student will have the opportunity to undergo project-specific training.

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to [Email Address Removed]

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Adult stem cell maintenance around the clock: do impaired stem cell clocks drive age-associated tissue degeneration?' 2018 Biogerontology 19(6):497-517

Comparing Circadian Dynamics in Primary Derived Stem Cells from Different Sources of Human Adult Tissue. Stem Cell Internatl 2017:2057168

Cellular mechano-environment regulates the mammary circadian clock. Nature Comm 2017 30 (8):14287

Ageing in relation to skeletal muscle dysfunction: redox homeostasis to regulation of gene expression. 2016 Mammalian Genome 27 (7-8): 341-357

The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. 2014 Genes & Development 28 (6): 548-60

miR-324-5p regulates Indian Hedgehog signalling by differing mechanisms in human and mouse and is up regulated in end-stage osteoarthritis. Matrix Biology 2019, 77, 87-100


Genome-wide microRNA and gene analysis of mesenchymal stem cell chondrogenesis identifies an essential role and multiple targets for miR-140-5p. Stem Cells 2015, 33(11), 3266-3280

Redox responses in skeletal muscle following denervation. Redox Biol 26:101294

Coordinated circadian timing through the integration of local inputs in Arabidopsis thaliana. PLoS Biol. 2019 17(8):e3000407

PeTTSy: a computational tool for perturbation analysis of complex systems biology models. BMC Bioinformatics. 2016 10;17:124



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