Circadian rhythms are present in species throughout the animal kingdom. In humans, disorders of circadian timing contribute to circadian-based sleep disorders, maladjustment of shift workers and during jet lag, and may contribute to neuropsychiatric disorders including depression and seasonal affective disorder. A transcriptional-translational feedback loop is at the center of the circadian clock mechanism. The known positive elements driving circadian transcription are CLOCK and BMAL1, two basic helix loop helix proteins that dimerize to activate expression of responsive genes. We have recently generated mice with a null mutation of the Clock gene. Unexpectedly, these CLOCK-deficient mice retain circadian rhythmicity in behavior in constant conditions. Our studies will characterize physiological and molecular rhythms in CLOCK-deficient mice, and assess mechanisms of rhythmicity in the absence of CLOCK. In mice with the previously described dominant negative mutation of Clock, the CLOCK-delta19 protein likely disrupts circadian rhythmicity by interfering with the activity of other key bHLH-PAS proteins, indicating that a major circadian transcriptional activator remains to be identified. A major objective of this project will be to identify this apparent second mechanism for transcriptional activation. We will test the hypothesis that NPAS2, a bHLH-PAS transcription factor closely related to CLOCK, can substitute for CLOCK and thus maintain rhythmicity in CLOCK-deficient mice. We will also determine whether BMAL1 is necessary for rhythmicity in the absence of CLOCK, expecting a finding that will enable studies based on assessment of the functional importance of candidate BMAL1-interacting proteins. The proposed studies are necessary to understand the function of CLOCK, a central component of the circadian clock mechanism, and thus are relevant to understanding and possibly developing novel treatments for circadian-based sleep and psychiatric disorders. In addition, the circadian clock plays diverse roles in regulating reproduction, metabolism, cell growth and tumor progression, so the importance of understanding basic mechanisms of circadian rhythm generation has many implications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056125-05
Application #
7812113
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Gnadt, James W
Project Start
2006-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$351,471
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Neurology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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van der Vinne, Vincent; Swoap, Steven J; Vajtay, Thomas J et al. (2018) Desynchrony between brain and peripheral clocks caused by CK1?/? disruption in GABA neurons does not lead to adverse metabolic outcomes. Proc Natl Acad Sci U S A 115:E2437-E2446
Stokes, Kyle; Cooke, Abrial; Chang, Hanna et al. (2017) The Circadian Clock Gene BMAL1 Coordinates Intestinal Regeneration. Cell Mol Gastroenterol Hepatol 4:95-114
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Dallmann, Robert; DeBruyne, Jason P; Weaver, David R (2011) Photic resetting and entrainment in CLOCK-deficient mice. J Biol Rhythms 26:390-401

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