This application seeks to determine the role of casein kinase in the mechanism of the circadian clock. Circadian clocks, while typically in synchrony with the daily environmental cycles of light and temperature, are generated endogenously in many organisms. In humans, the clocks control sleep-wake behavior as well as other physiological fluctuations. Disruptions of the circadian clock lead to sleep disorders, jet lag and a general malaise. Much of the population is forced to work shifts that are not in phase with their circadian clocks, thereby leading to physical and cognitive deficits that impact the health of the individuals and the quality of their work. Therefore, an understanding of the circadian mechanism will contribute to our ability to control the circadian clock for the benefit of affected individuals and of society. Much of our current knowledge about the mechanism of the circadian clock has come from a genetic analysis in fruit flies, which have a circadian mechanism quite similar to the human mechanism. For instance, the doubletime casein kinase (DBT) is thought to regulate the cytoplasmic and nuclear accumulation of another clock protein (PER) in both fruit flies and man. The work proposed here seeks to determine whether DBT's effects are regulated by other factors, and how its activity contributes to the accumulation of PER. In the first specific aim, the mechanism for the alteration of circadian period by several dbt mutations will be further investigated. In the second specific aim, the way in which DBT affects the stability of PER will be addressed by expressing wild type and mutated DBT and PER in a Drosophila cell line (S2). The phosphorylation of PER and the presence of DBT- and PER-interacting factors will also be assessed with in vitro and proteomic approaches, including a mass spectrometry analysis of proteins isolated from S2 cells. Finally, in a third specific aim, mutant forms of PER and DBT will be expressed as transgenes in flies, in order to elucidate the role of DBT in vivo. A vertebrate casein kinase I will be employed along with Drosophila DBT for specific aims 2 -3

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Biological Rhythms and Sleep Study Section (BRS)
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Beckel-Mitchener, Andrea C
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University of Missouri Kansas City
Schools of Arts and Sciences
Kansas City
United States
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Fan, Jin-Yuan; Preuss, Fabian; Muskus, Michael J et al. (2009) Drosophila and vertebrate casein kinase Idelta exhibits evolutionary conservation of circadian function. Genetics 181:139-52
Yu, Wangjie; Zheng, Hao; Price, Jeffrey L et al. (2009) DOUBLETIME plays a noncatalytic role to mediate CLOCK phosphorylation and repress CLOCK-dependent transcription within the Drosophila circadian clock. Mol Cell Biol 29:1452-8
Muskus, Michael J; Preuss, Fabian; Fan, Jin-Yuan et al. (2007) Drosophila DBT lacking protein kinase activity produces long-period and arrhythmic circadian behavioral and molecular rhythms. Mol Cell Biol 27:8049-64
Constance, Cara M; Fan, Jin-Yuan; Preuss, Fabian et al. (2005) The circadian clock-containing photoreceptor cells in Xenopus laevis express several isoforms of casein kinase I. Brain Res Mol Brain Res 136:199-211