Principal Supervisor: Professor Bruno Frenguelli, School of Life Sciences
Co-supervisor: Dr. Robert Dallmann, Warwick Medical School
PhD project title: Regulation of circadian behaviour by MSK1 (In vivo skills-appropriate project)
University of Registration: University of Warwick
Circadian clocks govern many aspects of physiological activity and can be found in virtually all cells. Dysregulation of circadian clocks, as found in shift workers and the elderly can lead to impaired cognition and a host of pathological conditions such as obesity and diabetes. As a consequence there is much interest in establishing the molecular basis of circadian clocks and the genes regulated in various tissues in a cyclical fashion.
There is evidence that a nuclear kinase, MSK1 is necessary for certain forms of clock resetting: MSK1 is found in the suprachiasmatic nuclei (SCN) and responds to light stimuli whereupon it may regulate clock gene expression and therefore contribute to entrainment.
In this project we will examine the role of MSK1 in the regulation of circadian clock on multiple levels through the use of a mutant mouse in which the kinase activity of MSK1 is disrupted. We will raise wild-type and MSK1 kinase-dead (KD) mice in standard housing conditions and probe the circadian system in vivo, as well as in vitro using fibroblasts as a model system for clock gene expression. In addition, we will utilise long-term in vivo and in vitro recordings of SCN and other tissues in bioluminescence circadian reporter mice with or without MSK1 mutation to monitor characterise the impact on MSK1-KD on the circadian clockwork. These studies will be complemented with studies in which mice are raised in an enriched environment where they can display more naturalistic behaviours through access to toys, running wheels, climbing frames and a larger number of cage-mates.
These studies are important as they will help to define the cellular and molecular mechanisms underpinning the regulation and plasticity of the mammalian circadian clock.
Cao R, et al (2013) Mitogen- and stress-activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock. Eur J Neurosci. 371:130-40.
Butcher GQ, et al., (2005) Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism. J Neurosci. 25:5305-13.
Hunter CJ et al., (2017) MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins. FEBS Open Bio. 7 821-834. doi: 10.1002/2211-5463.12232.
Daumas S et al., (2017) The kinase function of MSK1 regulates BDNF signaling to CREB and basal synaptic transmission, but is not required for hippocampal LTP or spatial memory. eNeuro. doi: 10.1523/ENEURO.0212-16.2017.
Correa, S.A., et al., (2012) MSK1 regulates homeostatic and experience-dependent synaptic plasticity. Journal of Neuroscience. 32 p.13039-51.
BBSRC Strategic Research Priority: Molecules, Cells and Systems
Techniques that will be undertaken during the project:
- Behavioural analysis
- Tissue and cell culture
- Next Generation Sequencing
- Quantitative biology/Bioinformatics
- Viral vector generation and viral gene delivery
- In vitro and in vivo bioluminescence reporter imaging
Contact: Professor Bruno Frenguelli, School of Life Sciences