Many organisms show daily oscillations of various physiological and behavioral processes, which are generated by a genetically determined circadian clock system. It is believed that the circadian system has evolved to provide the most efficient responses to changing environmental stimuli. Disruptions of circadian rhythms are often associated with pathological conditions; on the other hand, many types of illnesses (heart attacks, stroke, asthma etc.) show patterns of daily variation. Responses to different medications, and therefore the efficiency of treatment, may be significantly affected by the functional status of the circadian clock system. At the molecular level, circadian rhythms are generated by periodic changes in the expression levels of large groups of genes regulated by the components of the molecular circadian oscillator. Currently accepted model of the molecular circadian oscillator is based on a transcription-translation negative feedback loop. However, this model cannot provide comprehensive explanation for the circadian rhythms phenomena. In fact, we have demonstrated that circadian transcriptional complex possesses both transactivation and transrepression properties. Based on these observations, we propose a new concept of circadian system organization, suggesting that active circadian repression plays an important role in oscillator's operation and circadian control of responses to the environment. The current program is devoted to: (i) study of the functional role of posttranslational modifications of circadian transcriptional regulators and identification of proteins that involved in these modifications; (ii) understanding of the basic molecular mechanisms of the activation/repression function of circadian transcriptional regulators; (iii) the development of potential pharmacological modulators of circadian system through the high throughput screening of the chemical libraries using cell-based readout system. The completion of this program should not only bring this problem to a new level of understanding but will also help defining new targets for pharmacological modulation of circadian rhythmicity. ? ? ?
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