Circadian clocks in the bodies of humans ensure that functions such as the sleep/wake cycle, body temperature, hormonal secretion, cardiovascular function, respiration and metabolism are timed correctly. There is an exceptionally high degree of conservation between the circadian clocks of mammals and insects and much of our current understanding of clock function in humans is based on studies of the genes and the molecular circuits of the clock in model organisms such as Drosophila. Transcriptional feedback circuits responsible for the autonomous pacemaker function of the Drosophila clock have been identified in detail, but much less is known about the pathways connecting these circuits to overt rhythms in physiology and behavior. This proposal is designed to test the hypothesis that the CLK/CYC transcription factor of the Drosophila clock circuits has direct transcriptional targets in the Drosophila brain that generate behavioral rhythms.
Specific Aims : (1) Transcriptional targets specific to the circadian transcription factor CLK/CYC will be identified with the use of a set of transgenic flies that allow expression of each of these transcription factors to be induced individually in clock-bearing cells. (2) Direct transcriptional targets for CLK/CYC will be identified by luciferase reporter assays and chromatin immunoprecipitation experiments performed in Drosophila S2 cells. (3) Locomotor and eclosion behavior phenotypes associated with primary transcriptional clock output in the brain will be determined with the use of transgenic flies. Significance: The insight provided by the proposed studies into the internal time keeping mechanisms of animals is not only relevant to diseases associated with disruptions of these mechanisms (sleep disorders, cancer, diabetes), but also more generally to diagnostic and treatment procedures involving bodily functions that show regular daily variations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM078339-02S1
Application #
7714889
Study Section
Special Emphasis Panel (ZRG1-NCF-D (09))
Program Officer
Tompkins, Laurie
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
2
Fiscal Year
2009
Total Cost
$29,261
Indirect Cost
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Goda, Tadahiro; Mirowska, Karolina; Currie, Jake et al. (2011) Adult circadian behavior in Drosophila requires developmental expression of cycle, but not period. PLoS Genet 7:e1002167
Sellix, Michael T; Currie, Jake; Menaker, Michael et al. (2010) Fluorescence/luminescence circadian imaging of complex tissues at single-cell resolution. J Biol Rhythms 25:228-32
Wijnen, Herman (2009) Circadian rhythms. A circadian loop asSIRTs itself. Science 324:598-9
Currie, Jake; Goda, Tadahiro; Wijnen, Herman (2009) Selective entrainment of the Drosophila circadian clock to daily gradients in environmental temperature. BMC Biol 7:49
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Wijnen, Herman; Young, Michael W (2008) The right period for a Siesta. Neuron 60:943-6