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

Description

PROJECT BACKGROUND: 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. 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 deterioration. Emerging data has shown that many environmental stimuli can reset circadian clocks via redox mechanisms, suggesting an important role for 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.

PROJECT GOALS & TRAINING: We have previously published that NRF2-mediated redox signalling is subject to circadian regulation. This new project will investigate the role of NRF2 in skeletal muscle stem cell maintenance, differentiation and ageing by examining its regulation of epigenetic and clock factors using human myogenic precursors and transgenic animal models. This project will use a range of cross-disciplinary and 'state-of the art' techniques in order to perform cutting-edge research, including analyses of protein expression (western blotting, immunohistochemistry, proteomics), gene expression (qPCR, RNAseq) and protein-DNA interactions (ChiP) and clock gene rhythms (real-time bioluminescent imaging). Epigenetic tools will be used to perform gain- or loss-of-function approaches. Mathematical modelling of molecular pathways will enable us to model key proteins involved in integrating spatial and timing cues that control stem cell function.

SUPERVISORY TEAMS: This exciting project is a cross-institutional collaboration between the University of Liverpool supervisory team-primary supervisor Dr Vanja Pekovic-Vaughan (circadian redox biology), Dr Aphrodite Vasilaki (muscle physiology), Prof Richard Barret-Jolley (electrophysiology), Dr Mirela Domijan (modelling) and supervisors at University of Newcastle, Prof David Young (epigenetics), Dr Daryl Shanley (systems biology), where the PhD student will have unique opportunities to undergo broad laboratory and cross-disciplinary training. 

Informal enquiries may be made to 

HOW TO APPLY

Applications should be made by emailing  with a CV and a covering letter, 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. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Application Details Form (Word document) to , noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Availability

Open to students worldwide

Funding information

Funded studentship

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Supervisors

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 Communications 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.
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.