The last decade has witnessed a revolution in our understanding of the molecular mechanism of circadian clocks in animals, including the identification of at least seven different genes that are essential elements of the circadian clock mechanism (Clock, Email, Perl, Per2, Cryptochromel, Cryptochrome2 and Casein kinase 1 epsilon). With the initial discovery of these clock genes came the realization and documentation that the capacity for circadian expression is widespread throughout the body. Most peripheral organs and tissues can express circadian oscillations in isolation, yet still receive and may require input from the dominant circadian pacemaker in the suprachiasmatic nucleus (SCN) in vivo. The existence of both central and peripheral circadian oscillators raises a number of novel questions and hypotheses concerning the integration of the system to control the behavioral state of the organism. These discoveries on the clock mechanism and the organization of the circadian system have provided a unique opportunity to apply cutting-edge technology to discover both chemical and genetic tools to manipulate circadian rhythms both in vitro and in vivo. Tissue-specific and conditional genetic tools will be used to determine the consequences of central vs. peripheral circadian rhythm dysfunction on behavioral state (Takahashi project). The discovery of small molecules (McKnight project) and molecular targets (Hogenesch project) will provide new tools for manipulating circadian rhythms. New alleles of the central clock components will be identified and characterized (Green project) which will provide new insight into the clock mechanism and will provide new ways to analyze the chemical and genetic tools identified in the McKnight and Hogenesch projects. These tools will also be analyzed at the cellular and organismal level (Menaker and Block project). Finally, circadian clock gene variants and circadian disorders in humans will be utilized to cross validate and analyze the chemical and genetic tools developed in the molecular, cellular and animal studies (Ptacek project). The discovery of molecules (small chemicals and genetic tools) should provide new opportunities for the eventual translation of our knowledge of circadian clocks to human behavior and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH074924-04
Application #
7503350
Study Section
Special Emphasis Panel (ZMH1-ERB-L (03))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2005-09-15
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$1,998,686
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Ehlen, J Christopher; Brager, Allison J; Baggs, Julie et al. (2017) Bmal1 function in skeletal muscle regulates sleep. Elife 6:
Yoo, Seung-Hee; Kojima, Shihoko; Shimomura, Kazuhiro et al. (2017) Period2 3'-UTR and microRNA-24 regulate circadian rhythms by repressing PERIOD2 protein accumulation. Proc Natl Acad Sci U S A 114:E8855-E8864
Lee, Ivan T; Chang, Alexander S; Manandhar, Manabu et al. (2015) Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms. Neuron 85:1086-102
DeBruyne, Jason P; Baggs, Julie E; Sato, Trey K et al. (2015) Ubiquitin ligase Siah2 regulates RevErb? degradation and the mammalian circadian clock. Proc Natl Acad Sci U S A 112:12420-5
Fan, Junmei; Zeng, Hongkui; Olson, David P et al. (2015) Vasoactive intestinal polypeptide (VIP)-expressing neurons in the suprachiasmatic nucleus provide sparse GABAergic outputs to local neurons with circadian regulation occurring distal to the opening of postsynaptic GABAA ionotropic receptors. J Neurosci 35:1905-20
Partch, Carrie L; Green, Carla B; Takahashi, Joseph S (2014) Molecular architecture of the mammalian circadian clock. Trends Cell Biol 24:90-9
Izumo, Mariko; Pejchal, Martina; Schook, Andrew C et al. (2014) Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant. Elife 3:
Mohawk, Jennifer A; Pezuk, Pinar; Menaker, Michael (2013) Methamphetamine and dopamine receptor D1 regulate entrainment of murine circadian oscillators. PLoS One 8:e62463
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
Yoo, Seung-Hee; Mohawk, Jennifer A; Siepka, Sandra M et al. (2013) Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152:1091-105

Showing the most recent 10 out of 58 publications