Circadian control of ROS homeostasis

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DESCRIPTION (provided by applicant): Reactive oxygen and nitrogen species (ROS/RNS) serve as important regulators of cellular signaling, metabolism and other molecular responses. Intracellular levels of ROS/RNS are tightly controlled, because an elevated ROS level results in oxidative stress, which is considered a major determinant of pathologies such as heart diseases, stroke, diabetes and cancer. We have demonstrated that the circadian transcriptional factor BMAL1 is directly involved in the control of ROS/RNS homeostasis and oxidative stress response in mouse and human cells, presumably through the control of expression of major antioxidant enzymes: PRDX1, PRDX6 and SOD1. The importance of BMAL1 as a regulator of ROS homeostasis is further supported by the fact that BMAL1 deficiency in mice results in early aging syndrome - significantly reduced lifespan and development of multiple pathologies - and is accompanied by elevated levels of ROS in several tissues. The treatment of BMAL1-null mice with the low molecular weight antioxidant NAC (N-acetyl cysteine) extends their lifespan and ameliorates pathologies. We hypothesized that the circadian system regulates ROS/RNS homeostasis and antioxidant defense by controlling BMAL1 expression/activity. We will determine molecular mechanisms of BMAL1-dependent regulation of ROS homeostasis and role of the circadian clock in the control this process through the following Specific Aims: (A1) To investigate the role of BMAL1 transcriptional targets PRDX1, PRDX6 and SOD1 in the BMAL1-dependent control of ROS homeostasis. (A2) To investigate the influence of circadian proteins CLOCK and CRY1 on the BMAL1-dependent regulation of ROS homeostasis. (A3) To investigate BMAL1-dependent ROS homeostasis and antioxidant defense in vivo. PUBLIC HEALTH RELEVANCE: This project addresses the role of the circadian clock proteins in the defense of organism from harmful action of free radicals. The obtained results will help to understand molecular basis of development of such pathologies as heart diseases, stroke and diabetes, and to develop a rational strategy for treatment and prevention.