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.
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