Mechanisms of slowpoke in regulating circadian behavior

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DESCRIPTION (provided by applicant): Numerous biological phenomena follow a daily cycling time course. Disturbances of circadian rhythms are linked to sleep disorders, cancer and neurological disorders. In addition, the circadian clock also controls many disease processes and physiological responses to medications. To better understand circadian clocks, we have carried out genome-wide analysis to identify clock-controlled genes in Drosophila and mouse. We found Drosophila slowpoke (slo) or its vertebrate homolog, Kcnmal, to be one of the few genes that is controlled by the clock in both species. A mutation of slo in flies results in aberrant rhythms in locomotor activity. This suggests that slo/Kcnmal plays an important role in regulating circadian behavior. The specific aims of this proposal are to first characterize slo-expressing cells by immunohistochemistry and in situ hybridization. Using the GAL4-UAS system, we will test the requirement of these cells for rhythmic locomotor activity. Second, through molecular, genetic and behavioral analyses, we will investigate the placement of slo in the genetic hierarchy of the circadian system. Our study will also extend to the physiological function of rhythmically expressed Kcnmal in the mouse pacemaker neurons. We will measure the effect of Kcnmal siRNAs on the firing rhythm of pacemaker cells. Together, understanding the functions of slo and Kcnmal is a key step linking the molecular "clock" to physiological and behavioral outputs. Given the ubiquity of circadian-regulated pathways and the importance of circadian cycles to the overall fitness of organisms and to human health, this study will ultimately assist the dissection of the human clock and clock-regulated activity.