BIOCHEM ANAL OF WC1--CIRCADIAN RHYTHM/LIGHT TRANSDUCTION

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DESCRIPTION (Applicant's abstract reproduced verbatim): Most organisms have an internal circadian clock which influences many aspects of daily activities. The disruption of the circadian clock in humans leads to several rhythmicity disorders including sleep disorders and psychiatric illnesses such as manic depression and Seasonal Affective Disorder. Recent clock studies in mammals have revealed that the circadian clock in mammalian systems appears to be based upon a paradigm similar to that established in the fungus Neurospora crassa and the insect Drosophila melanogaster. The current basic paradigm for the cellular oscillator is a transcriptional/ translational feedback loop, which is composed of negative (FRQ in Neurospora, PER in Drosophila and mPER1, mPER2 and mPER3 in mammals) and positive elements (WC1 and WC2 in Neurospora, dCLOCK and CYC in Drosophila, and CLOCK and BMAL1 in mammals). The key positive elements in the feedback loop contain PAS domains, through which they form homo- or hetero-dimers. WC1 is, so far, the only known PAS-containing protein that plays a role both in light reception and in circadian rhythms. The research in this application is aimed at answering the following questions: 1) What are the roles of FRQ and WC1 in each other's expression? 2) What are the components of the WC1 complex in constant dark (where the free running oscillation can be studied) and after a light pulse? 3) What is the significance of the PAS domain in the operation of the circadian feedback loop and in the light signal transduction?