Control of peripheral circadian rhythms (full)

We are investigating how circadian clocks (biological clocks with a period of about 24 hours), control daily cycles of physiology in mice. The body’s master circadian clock is located in a small group of cells in the hypothalamus of the brain (the suprachiasmatic nuclei or SCN) and is synchronised to the 24 hour day by daily cycles of light and darkness. However, other organs such as heart and liver also contain circadian clocks, which exert local control over daily rhythms of physiology and metabolism. Many of these peripheral clocks are thought to be controlled by the timing of food intake. We are establishing the roles of circadian clocks in the SCN and in peripheral organs in the regulation of blood pressure, heart rate, energy metabolism and hormone secretion. It is thought that the activity of peripheral circadian clocks may underlie profound daily variations in the severity of many common human diseases such as arthritis, asthma and cardiovascular disease. The work may lead to a better understanding of the mechanisms underlying circadian variations in human diseases, may identify new approaches to reduce such risks and may suggest improvements to conventional treatments in which the timing of drug use is matched to the circadian rhythm of the illness.

Circadian rhythms are regular cycles of physiology, metabolism and behaviour, with a period of about 24 hours, which persist in the absence of environmental cues. Daily variations in normal human physiology, such as sleep-wake cycles and blood pressure, as well as the symptoms of many diseases, for example asthma, cardiovascular disease and stroke, are believed to be under circadian control. The ?master clock? driving mammalian circadian rhythms is a light-entrainable circadian oscillator system (LEO) located in the suprachiasmatic nuclei (SCN) of the hypothalamus. However, many peripheral tissues also contain endogenous circadian clocks, which exert local control over rhythms of physiology and metabolism (for example, rhythms in the expression of genes involved in the processing of food and in drug detoxification in the liver). The clocks in many peripheral organs are thought to be controlled by a food-entrainable oscillator (FEO), which is probably located in the brain, but is distinct from the LEO in the SCN. The FEO is also responsible for a circadian timing mechanism that causes animals to become active in anticipation of scheduled feeding. We propose to establish the roles of the FEO and the LEO in the regulation of circadian clocks in peripheral tissues, with special emphasis on their effects on energy metabolism and the hypothalamo-pituitary-adrenal (HPA) axis. Our general approach will be to explore the influence of controlled lighting and feeding regimes on rhythms of behaviour, physiology, endocrinology and gene expression in a variety of mouse mutant strains. These will include Vipr2 null mice, in which the LEO is disabled but robust rhythms of gene expression are seen in peripheral tissues, and Npas2 null mice, in which control of the FEO is impaired. Breeding of Vipr2 and/or Npas2 null mice to a transgenic line carrying a clock-driven luciferase reporter gene will allow monitoring of circadian activity by bioluminescence. Radiotelemetry will be used to determine how physiological parameters such as blood pressure, heart rate and body temperature are influenced by the circadian activity of peripheral oscillators.