Sleep is controlled by two processes: a homeostatic drive that increases during waking and dissipates during sleep and a circadian pacemaker that controls its timing. Although these two systems can operate independently recent studies suggest a more intimate relationship. Indeed, none has been as dramatic as that found for the canonical loss-of-function clock mutant cycle (cyc01). cyc01 mutants showed a disproportionately large sleep rebound and died following 10 hours of sleep deprivation, although they were more resistant than other clock mutants to various stressors. Our data indicate that the pathology is characterized by an acceleration of the detrimental effects of waking and furthermore, suggests that these processes subsequently increase the need for sleep (Shaw et al., 2002). Using genomic studies in these uniquely sensitive animals, we have begun to identify functional targets of sleep homeostasis and its molecular mechanisms. Thus we know of 100 genes that are modulated by prolonged wakefulness. In order to more fully understand the role these genes play, we will determine their temporal dynamics in response to increasing amounts of waking. Moreover, because we have developed independent genetic, pharmacological and behavioral assays that produce periods of waking that differentially activate homeostatic responses, we will determine the extent to which these genes are specifically associated with homeostasis. More importantly, we have acquired over 110 mutant lines representing approximately 60 of the 100 genetic loci of interest and have begun to evaluate their sleep parameters and responses to sleep deprivation. We propose to characterize select genes further by localizing mRNA and protein expression and to manipulate the activity of these genes and the cells that express them by creating a variety of useful transgenic lines using UAS, GAL4 and GAL80 vectors.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BRS (01))
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Mitler, Merrill
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Washington University
Schools of Medicine
Saint Louis
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