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How do circadian and behaviour-driven metabolite rhythms influence health and ageing in humans

Principal Supervisor: Professor Warwick Dunn, School of Biosciences, University of Birmingham

Co-supervisor: Dr Robert Dallmann, Warwick Medical School, University of Warwick

PhD project title: How do circadian and behaviour-driven metabolite rhythms influence health and ageing in humans

University of Registration: University of Birmingham

Project outline:

Introduction and project rationale: Endogenous circadian rhythms are key in many physiological and behavioural processes in humans and changes in rhythms or desynchronization processes (for example, in shift workers) have been linked with adverse outcomes related to health and ageing. The central circadian clock is located in the hypothalamic suprachiasmatic nuclei and synchronises the timing of peripheral clocks in liver, muscle, gut and adipose tissue. Previous research has suggested that the central and peripheral circadian clocks are highly synchronised but recent research has implicated that misalignment between the central and peripheral clocks is a driver in ageing and development of chronic non-communicable diseases including obesity and type 2 diabetes. Understanding how the central and peripheral circadian clocks regulate metabolism or how these clocks are regulated by metabolic processes is hugely important, though limited research has currently been performed.

PhD research objectives:

Primary objective: To define the feedback and feed-forward links between the circadian timing system and metabolism in humans applying metabolomics and cellular molecular biology approaches

Secondary objectives: To experimentally define (1) how the central circadian clock in young and older healthy humans regulates metabolism or is regulated by metabolism; (2) how the peripheral circadian clocks in healthy humans regulates metabolism or is regulated by metabolism; (3) how acute and chronic changes to the central circadian clock effects peripheral clocks.

Research team:The supervisory team is built with experts in the areas of metabolism, metabolomics and statistical modelling (Professor Dunn, University of Birmingham), cellular molecular biology (Dr Dalmann, University of Warwick) and chronobiology (Professor Debra Skene, University of Surrey).

Methods to be applied:During your PhD you will receive training in complementary and inter-disciplinary research skills including metabolomics, chronobiology, statistical analysis, network modelling and subject recruitment and study design. The research will be primarily based at the University of Birmingham in the group of Professor Dunn with placements at the University of Warwick and the University of Surrey.

References:

  1. Dunn, W.B., Broadhurst, D.I., Atherton, H.J., Goodacre, R. and Griffin, J.L., 2011. Systems level studies of mammalian metabolomes: the roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chemical Society Reviews, 40(1), pp.387-426.
  2. Davies, S.K., Ang, J.E., Revell, V.L., Holmes, B., Mann, A., Robertson, F.P., Cui, N., Middleton, B., Ackermann, K., Kayser, M. and Thumser, A.E., 2014. Effect of sleep deprivation on the human metabolome. Proceedings of the National Academy of Sciences, p.201402663.
  3. Schmitt, K., Grimm, A., Dallmann, R., Oettinghaus, B., Restelli, L.M., Witzig, M., Ishihara, N., Mihara, K., Ripperger, J.A., Albrecht, U. and Frank, S., 2018. Circadian control of DRP1 activity regulates mitochondrial dynamics and bioenergetics. Cell metabolism, 27(3), pp.657-666.

BBSRC Strategic Research Priority: Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  1. Metabolomics: use of liquid chromatography-mass spectrometry platforms for collection of data related to the concentration of tens to thousands of metabolites in human blood, urine and tissues (in Dunn research team)
  2. Statistical analysis and mathematical modelling: use of univariate and multivariate data analysis tools to dissect complex metabolic-phenotypic datasets and identify casual relationships (in Dunn research group)
  3. Molecular biology techniques: use of targeted assays for analysis of proteins and RNA in cellular and tissue samples (in Dallmann research group)
  4. Design of projects involving humans: use of highly controlled circadian and sleep laboratory protocols to define the role of behaviour (feeding/fasting; sleep/wake), the environment (light/dark) and the circadian timing system on metabolic profiles (in Skene research team)

Contact: Professor Warwick Dunn, University of Birmingham