Chemical and Genetic Manipulation of Circadian Systems

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DESCRIPTION (provided by applicant): 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.