The circadian clock regulates physiology and behavior and impinges on many aspects of our daily life. Nowhere is this more obvious than control of the sleep wake cycle, where clock genes have been shown to play a role in both the timing of sleep and its quality. For example, mutations in PER2 cause familial advanced sleep phase syndrome (FASPS), while mutations in CSNK1E and CSNK1D cause FASPS and delayed sleep phase syndrome (DSPS), respectively. However, while we have learned much about the clock and how it regulates sleep, the picture is incomplete. Behavioral studies in mice and studies in human cells show that dozens to hundreds of loci impact circadian clock function. However, only a dozen genes have been investigated for their roles in regulating behavior. Testing dozens to hundreds of mice isn't practical, so a new approach is needed. Here we seek to address this gap with a novel strategy that uses, i) integrative bioinformatics to prioritize putative core clock factors, ii) new experimental methods to determine whether they interact with known clock genes and regulate clock function in several cellular or tissue slice models, and, finally, iii) for a subset of promising candidates, generate mouse models and test them for their roles in regulating circadian behavior and sleep. Completion of this research will improve our understanding of circadian rhythms and sleep and may point the way to new therapeutic targets for related disorders in humans.

Public Health Relevance

Our internal biological clocks control many important aspects of our physiology and behavior such as the sleep-wake cycle. Genetics and large-scale genomic studies have implicated the role of a dozen canonical and hundreds of additional new genes in the circadian clock. However, almost none of the new genes have been studied in animal models for their ability to regulate sleep onset or quality. We will address this gap using bioinformatics, experimental biology, and finally through behavioral analysis. Completion of this research will improve our understanding of circadian rhythms and sleep and may point the way to new therapeutic targets for related disorders in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS054794-11
Application #
9349043
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (05)M)
Program Officer
He, Janet
Project Start
2007-05-01
Project End
2017-04-30
Budget Start
2016-09-01
Budget End
2017-04-30
Support Year
11
Fiscal Year
2015
Total Cost
$386,756
Indirect Cost
$138,835
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Yang, Yanyan; Adebali, Ogun; Wu, Gang et al. (2018) Cisplatin-DNA adduct repair of transcribed genes is controlled by two circadian programs in mouse tissues. Proc Natl Acad Sci U S A 115:E4777-E4785
Foteinou, Panagiota T; Venkataraman, Anand; Francey, Lauren J et al. (2018) Computational and experimental insights into the circadian effects of SIRT1. Proc Natl Acad Sci U S A 115:11643-11648
Wu, Gang; Ruben, Marc D; Schmidt, Robert E et al. (2018) Population-level rhythms in human skin with implications for circadian medicine. Proc Natl Acad Sci U S A 115:12313-12318
Giovannone, Adrian J; Winterstein, Christine; Bhattaram, Pallavi et al. (2018) Soluble syntaxin 3 functions as a transcriptional regulator. J Biol Chem 293:5478-5491
Anafi, Ron C; Francey, Lauren J; Hogenesch, John B et al. (2017) CYCLOPS reveals human transcriptional rhythms in health and disease. Proc Natl Acad Sci U S A 114:5312-5317
Hughes, Michael E; Abruzzi, Katherine C; Allada, Ravi et al. (2017) Guidelines for Genome-Scale Analysis of Biological Rhythms. J Biol Rhythms 32:380-393
Krishnaiah, Saikumari Y; Wu, Gang; Altman, Brian J et al. (2017) Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism. Cell Metab 25:961-974.e4
Francey, Lauren J; Hogenesch, John B (2017) It's not all in the brain. Elife 6:
Ruben, Marc D; Hogenesch, John B (2017) Circadian Rhythms: Move Over Neurons - Astrocytes Mediate SCN Clock Function. Curr Biol 27:R350-R352
Love, Michael I; Hogenesch, John B; Irizarry, Rafael A (2016) Modeling of RNA-seq fragment sequence bias reduces systematic errors in transcript abundance estimation. Nat Biotechnol 34:1287-1291

Showing the most recent 10 out of 56 publications