Hypersomnia is a sleep disorder in which patients have a prolonged nighttime sleep episode from which it is difficult to awaken and/or excessive daytime sleepiness. Hypersomnia can have a number of underlying causes, some of which are related to improper phasing of the daily biological clock, such as in the cases of Delayed & Advanced Sleep Phase Syndromes. In addition, there are temporary hypersomnias associated with shiftwork and jet lag that are also related to the daily clock. Both recurrent and temporary hypersomnias, while not life threatening, can have serious consequences. This project will discover therapeutics for treating the subset of hypersomnias that are related to the biological clock. At the present time, there are practically no pharmacological treatments that can be used to specifically manipulate these biological clocks. Novel chemical compounds that directly affect the phase and period of biological clocks in mammalian cells for use as """"""""chronotherapeutics"""""""" will be identified by using the newly developed system of mammalian fibroblasts that are stably transfected with luminescence reporters so that they glow rhythmically under the behest of their biological clock. These cells will be used in an automated high- throughput screen to identify compounds from the Vanderbilt Institute of Chemical Biology's library of ~150,000 chemically synthesized compounds that reset the phase and/or modulate the activity of the biological clock. Subsequent screens will test the efficacy of candidate compounds on the clock in brain and other tissue slices in vitro and intact mice in vivo. This project is appropriate for the NINDS Exploratory/Developmental Grant (R21) Program in Translational Research because it will develop screens at cellular, tissue, and organismal levels (including high-throughput screens) for discovering candidate therapeutics that will lead directly to the development of therapies for hypersomnias and other sleep disorders that are clock-related. TO PUBLIC HEALTH: This project will provide pharmacological tools for manipulating the phasing of the biological clock systems in mammals that will lead to the identification of a chrono- pharmacopoeia for treating recurrent and temporary hypersomnias (and other sleep disorders) that are caused by improper phasing of the biological clock in humans. ? ? ?
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