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Signalling within the mammalian circadian timing system

Objective

The main objective of this interdisciplinary research project is to elucidate regulatory mechanisms through which the circadian timing system coordinates temporal physiology. This system has a hierarchical architecture, in that a master clock in the brain s suprachiasmatic nucleus synchronizes subsidiary oscillators in nearly all body cells. The establishment of phase coherence is obviously of utmost importance in the coordination of circadian physiology. While recent studies have identified feeding cycles, hormone rhythms, and body temperature oscillations as timing cues for peripheral clocks, the molecular makeup of the involved signalling mechanisms is largely unknown. Using liver and cultured cells as model systems, we will employ two innovative strategies for the elucidation of relevant signalling pathways. (1) STAR-Prom (Synthetic TAndem Repeat-PROmoter display), a technique developed in our laboratory, will hopefully identify most if not all immediate early transcription factors activated in cultured cells by rhythmic blood-borne and temperature-dependent signals. (2) A transgenic mouse model with conditionally active liver clocks will be explored in the genome-wide identification of coding and non-coding transcripts whose rhythmic accumulation is system-driven. The in vivo significance of the components emerging from these approaches will be assessed via RNA interference. Thus, relevant siRNAs will be injected into the tail vein of mice, and their effect on the phase of circadian liver gene expression will be monitored in freely moving mice by using whole body fluorescence imaging. Physiologically important components will serve as entry points for the identification of upstream and downstream constituents in the corresponding signal transduction cascades.

Field of science

  • /medical and health sciences/basic medicine/physiology

Call for proposal

ERC-2009-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

UNIVERSITE DE GENEVE
Address
Rue Du General Dufour 24
1211 Geneve
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 360 136
Principal investigator
Ulrich Schibler (Prof.)
Administrative Contact
Alex Waehry (Dr.)

Beneficiaries (1)

UNIVERSITE DE GENEVE
Switzerland
EU contribution
€ 2 360 136
Address
Rue Du General Dufour 24
1211 Geneve
Activity type
Higher or Secondary Education Establishments
Principal investigator
Ulrich Schibler (Prof.)
Administrative Contact
Alex Waehry (Dr.)