Living organisms have evolved mechanisms to synchronize metabolic and physiological functions with the ~24 hour light/dark cycle. When traveling across time zones, our sleep-wake patterns, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of being """"""""out of phase"""""""" until we adjust to the new time zone. In addition, recent studies have also linked disruption of the circadian clock with numerous ailments, including: asthma, cancer, and cardiovascular diseases. Much knowledge has come from studying the genetic and molecular basis of circadian rhythms in model organisms. Despite the importance of the circadian clock, the opportunity to probe the human circadian clock only became possible with the recognition of a Mendelian circadian variant in people (familial advanced sleep-phase syndrome, FASPS). In the initial funding period of this grant, we characterized FASPS, collected 3 families, and mapped and cloned the first FASPS gene. During the current grant period, we've 1) begun to identify and collect familial delayed sleep phase syndrome (FDSPS) families and >40 additional FASPS kindreds;2) identified 5 novel human circadian rhythm genes and mutations causing FASPS in our first 22 FASPS families;3) performed in vitro biochemical and cell biological experiments to understand functional consequences of these mutations;and 4) generated mouse models (and begun to characterize circadian phenotypes) of FASPS mutations in 4 human circadian rhythm genes (Per2, CKId, CKIe, and Dec2). In this competitive renewal, we propose to expand collection of our families (Aim 1), to identify FDSPS mutations (Aim 2), to genetically map novel human circadian rhythm loci (Aim 3), and to characterize circadian phenotypes of all 4 FASPS mouse models in greater detail (Aim 4). We will also enroll mutation positive FASPS subjects into a protocol to measure period, phase, and phase angles. Parallel studies in humans and mice will synergize in our efforts to dissect understanding of FASPS in humans and exploring the similarities and differences between our clocks vs. those of other organisms. Studying the molecular mechanism of human clock will have an enormous impact on our understanding of human health &disease and lead to new strategies for pharmacological manipulation to improve the treatment of jetlag, various clock-related sleep and psychiatric disorders.

Public Health Relevance

Through study of naturally occurring mutations in humans with strong 'morning lark'or 'night owl'sleep wake patterns, we are learning about basic mechanisms of human circadian/sleep regulation. Such insights will identify targets for developing better therapies for sleep disorders including shift work and jetlag.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059596-13
Application #
8091290
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Laposky, Aaron D
Project Start
1997-09-30
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
13
Fiscal Year
2011
Total Cost
$531,369
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Shi, Guangsen; Wu, David; Ptá?ek, Louis J et al. (2017) Human genetics and sleep behavior. Curr Opin Neurobiol 44:43-49
Hirano, Arisa; Braas, Daniel; Fu, Ying-Hui et al. (2017) FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice. Cell Rep 19:255-266
Zhang, Luoying; Hirano, Arisa; Hsu, Pei-Ken et al. (2016) A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. Proc Natl Acad Sci U S A 113:E1536-44
Hirano, Arisa; Shi, Guangsen; Jones, Christopher R et al. (2016) A Cryptochrome 2 mutation yields advanced sleep phase in humans. Elife 5:
Hirano, Arisa; Fu, Ying-Hui; Ptá?ek, Louis J (2016) The intricate dance of post-translational modifications in the rhythm of life. Nat Struct Mol Biol 23:1053-1060
Hsu, Pei-Ken; Ptá?ek, Louis J; Fu, Ying-Hui (2015) Genetics of human sleep behavioral phenotypes. Methods Enzymol 552:309-24
Lin, Shu-Ting; Zhang, Luoying; Lin, Xiaoyan et al. (2014) Nuclear envelope protein MAN1 regulates clock through BMAL1. Elife 3:e02981
Kaasik, Krista; Kivimäe, Saul; Allen, Jasmina J et al. (2013) Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab 17:291-302
Zhang, Luoying; Ptá?ek, Louis J; Fu, Ying-Hui (2013) Diversity of human clock genotypes and consequences. Prog Mol Biol Transl Sci 119:51-81
Hallows, William C; Ptá?ek, Louis J; Fu, Ying-Hui (2013) Solving the mystery of human sleep schedules one mutation at a time. Crit Rev Biochem Mol Biol 48:465-75

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