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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM070975-03
Application #
6924719
Study Section
Special Emphasis Panel (ZRG1-F02A (20))
Program Officer
Portnoy, Matthew
Project Start
2003-09-01
Project End
2006-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$49,928
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037