The molecular components of mammalian circadian clocks are elusive. The applicant has isolated a human gene termed RIGUI that encodes a bHLH/PAS protein 44 percent homologous to the period gene in Drosophila. The highly conserved mouse homolog (m-rigui) is expressed in a circadian pattern in the suprachiasmatic nucleus (SCN), the master regulator of circadian clocks in mammals. Circadian expression in the SCN continues in constant darkness, and a shift in the light/dark cycle evokes a proportional shift of m-rigui expression in the SCN. m-rigui transcripts also appear in a periodic pattern in Purkinje neurons, pars tuberalis, and retina, but with a timing of oscillation different from that seen in the SCN. Given the observation that the RIGUI gene has all the properties known about a core circadian component the principal investigator would like to define better its exact role in the circadian pathway.
The specific aims of this study are to: a) Identify specific brain and peripheral tissue where the various circadian oscillators reside; b) Determine whether melatonin plays a role in the expression of m-rigui in the hypophyseal pars-tuberalis; c) Investigate the response of m-rigui expression in the retina and suprachiasmatic nucleus to environmental light cues; d) Make the targeted disruption of the m-rigui locus by gene knock-out methodology and determine the effect of its loss on the circadian behavior of the animals; e) Identify genes encoding proteins that interact with RIGUI using the two-hybrid system; f) Determine the genomic structure of the human RIGUI locus and delineate its promoter and cis-acting elements. Understanding genetics and molecular basis of RIGUI function could lead to new paradigms on how genes control mammalian behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037917-02
Application #
2892456
Study Section
Neurology C Study Section (NEUC)
Program Officer
Kitt, Cheryl A
Project Start
1998-07-15
Project End
2002-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030