Many physiological and behavioral processes show circadian rhythms, which are generated by an internal, genetically determined time-keeping system, the biological clock. At the molecular level, circadian clock system is based on a periodic transcriptional activation/repression of a set of genes that form the core oscillator and subsequently drive recurrent rhythms in RNA of many target genes, thus generating the output 24-hr periodicities. The proposed program is based on the observation that, among other processes, circadian clock system modulates in vivo sensitivity to genotoxic stress induced by two different cancer therapeutic agents - cyclophosphamide and gamma radiation. The ultimate goal of this program is the identification of molecular mechanisms of circadian control that could be used for rationale modulation of anticancer treatment. It will be primarily focused on gamma radiation induced responses, which is a well-studied system for both its in vivo effects and at the level of molecular mechanisms. For this study we are introducing the new genetic model system - mice with disrupted circadian function due to deficiency of circadian system activators (Bmal1-/- mutants) or deficiency of circadian system inhibitors (Cry1Cry2 -/- mutants). This genetic model system will be used to address both aspects of cancer therapy, combination of which determine its therapeutic index - the level of tumor response to treatment as a function of its circadian status, and the amount of damage caused to normal tissues as a result of genetically deregulated circadian control. The radiation response at different circadian background will be compared both in vivo and in variety of newly developed circadian cell model systems. Such an approach will not only advance our understanding the important role of circadian system in regulating sensitivity to cancer therapy, but will also form a basis for identification of molecular determinants that may be used as targets for pharmacological modulation of radiation sensitivity.
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