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Cellular rhythms, signalling and metabolic regulation

John O'Neill

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Medical Research Council (MRC)
Circadian (about daily) rhythms are cell-intrinsic phenomena that permeate every level of biology, affecting many aspects of health and disease. In humans the sleep/wake cycle is overtly circadian-regulated, as are numerous aspects of physiology and metabolism. Circadian disruption, as occurs in shift work, increases the risk of chronic illnesses such as type II diabetes, cardiovascular disease and cancer. The mechanism and significance of cellular clocks is therefore an important biological question. In previous work we have shown that, whilst cycles of nascent ‘clock gene’ expression are required for rhythmic behaviour and physiology, they are insufficient to account for circadian rhythms at the cellular level. To better understand the underlying clock machinery therefore, we break the problem down into three complementary questions: Cause – What is the cellular clock mechanism? Using pharmacological, metabolic and genetic manipulations, with real-time reporters and mass spectrometry, we perturb the cellular clock in order to identify the minimal set of components they require. Consequence – How do cellular clocks interact with other biological systems? Many biological processes are circadian-regulated but in few cases have the causal relationships, from cellular rhythm to phenotype, been clearly delineated. We investigate how internal timekeeping influences processes such as wound healing and neuronal function from a bottom-up perspective. Comparative Chronobiology – How did biological clocks evolve? By comparing the daily rhythms in mammalian cells with circadian or ultradian rhythms in evolutionary distant eukaryotes, we can distinguish fundamental timekeeping components from species-specific adaptations and so gain insight from highly conserved molecular mechanisms.

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