A master circadian clock resides in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus of mammals. Recent discoveries in this and other laboratories have identified a molecular framework for the core clock mechanism in the SCN. The core mechanism involves a transcriptional/translational feedback loop that has both positive and negative components. The positive aspects appear to involve the transcriptional activation of a family of three mouse (m) Per genes by CLOCK-BMAL1 heterodimers acting through a CACGTG E box. The negative aspect of the core feedback loop appears to involve the three mPER proteins and a recently identified mTIM protein. This proposal is directed at defining the molecular details of the core feedback loop in the mouse SCN using genetic, molecular, biochemical and behavioral approaches.
The specific aims will 1) define the positive transcriptional elements that regulate the three mPer genes; 2) elucidate the molecular mechanisms involved in the negative limb of the core feedback loop; 3) evaluate temporal phosphorylation of the mPERs; and 4) examine the effects of targeted deletion of the mPer and mTim genes on circadian behavior and the molecular feedback loop. A long-term goal of this Research Plan is to define the cellular and molecular mechanisms that underlie circadian rhythms. The proposed studies provide an integrated approach that will supply important information about defined circadian clock components and their mechanisms of action in the SCN. Increased understanding of the fundamental mechanisms of biological clock function will facilitate the development of better treatment strategies for a wide range of disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039303-05
Application #
6625477
Study Section
Special Emphasis Panel (ZRG1-IFCN-3 (01))
Program Officer
Mitler, Merrill
Project Start
1999-12-24
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
5
Fiscal Year
2003
Total Cost
$331,193
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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