Control of peripheral circadian rhythms (full)

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health

Abstract

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.

Technical Summary

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.

Publications

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Pakhotin P (2006) VIP receptors control excitability of suprachiasmatic nuclei neurones. in Pflugers Archiv : European journal of physiology

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Sheward WJ (2007) Entrainment to feeding but not to light: circadian phenotype of VPAC2 receptor-null mice. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description BHF Project Grant
Amount £140,668 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 09/2011
 
Description Collaboration with MRC Laboratory of Molecular Biology 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Supplied materials, suggested experiments, contributed to manuscripts and response to referees
Collaborator Contribution Suggested experiments, contributed to manuscripts and response to referees
Impact PMID: 16546085 PMID: 17442819
 
Description Collaboration with University of Aberdeen 
Organisation University of Aberdeen
Department Institute of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributed materials, suggestions of experiments and contributed to a manuscript
Collaborator Contribution Contributed ideas for future research
Impact PMID: 16823490
 
Description Collaboration with University of Manchester 
Organisation University of Manchester
Department Faculty of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributed materials, suggested experiments, contributed to manuscript
Collaborator Contribution Contributed ideas and concepts for future research through collaborative work
Impact PMID: 16283205
 
Description Collaboration with University of Southampton 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Conctibuted materials, suggested and performed experiments, contributed to a manuscript
Collaborator Contribution Collaborative work that may lead to future joint applications for funding
Impact PMID: 19650041
Start Year 2008
 
Description Schools Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Lecture on "biological clocks" (including a description of our work) at Edinburgh Academy as part of their James Clerk Maxwell Science Lecture series

N/A
Year(s) Of Engagement Activity 2007