Over the past decade, tremendous progress has been made in our understanding of the molecular mechanism of circadian clocks in mammals. Circadian oscillations are generated by a set of genes that form a transcriptional autoregulatory feedback loop. In mammals, there are at least seven different genes that have been proposed as 'core'circadian elements of the clock mechanism. Despite this remarkable progress, it is clear that a significant number of genes that regulate circadian rhythms in mammals remain to be discovered and identified. Forward genetic screens have been the most effective tool for circadian gene discovery, and we have used this approach to screen the mouse genome for circadian rhythm mutants in the Neurogenomics Project in the Center for Functional Genomics at Northwestern University. Over 60 new circadian mutants were identified as part of a large-scale ENU mutagenesis screen to create a mutant mouse resource for nervous system and behavioral phenotypes.
Our specific aims are: 1. To identify the gene responsible for the 'Overtime'circadian period mutant in mouse. We will test the hypothesis that the 'Overtime'mutant represents a novel circadian rhythm gene. 2. To determine the genetic map position of twenty of the most robust circadian mutants isolated in our large- scale mutagenesis screen. To provide a more valuable research tool for the circadian research community, we propose to map 20 new circadian mutants. 3. To characterize and identify the 'swing-shift'mutant which is a novel entrainment mutant in mice. We will clone the 'swing-shift'mutant and test the hypothesis that 'swing-shift'mice have either a molecular or an anatomical lesion in the photic input pathway into the suprachiasmatic nucleus. Characterization of these novel circadian mutants and the identification of the causative genes should provide new insight into the mechanism of the mammalian circadian clock.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH078024-04
Application #
8145381
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-09-23
Budget End
2011-04-30
Support Year
4
Fiscal Year
2010
Total Cost
$360,482
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
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