Circadian control of ROS homeostasis

描述(申请人提供)：活性氧和氮物种(ROS/RNS)是细胞信号、新陈代谢和其他分子反应的重要调节者。细胞内ROS/RNS水平受到严格控制，因为ROS水平升高会导致氧化应激，氧化应激被认为是心脏病、中风、糖尿病和癌症等病理的主要决定因素。我们已经证明，昼夜节律转录因子BMAL1直接参与控制小鼠和人类细胞的ROS/RNS动态平衡和氧化应激反应，可能是通过控制主要抗氧化酶PRDX1、PRDX6和SOD1的表达。BMAL1作为ROS稳态调节因子的重要性进一步得到了以下事实的支持：小鼠缺乏BMAL1会导致早期衰老综合征-显著缩短寿命和发展多种病理-并伴随着几个组织中ROS水平的升高。用低分子抗氧化剂NAC(N-乙酰半胱氨酸)治疗BMAL1基因缺失的小鼠可延长其寿命并改善其病理状态。我们假设昼夜节律系统通过控制BMAL1的表达/活性来调节ROS/RNS的动态平衡和抗氧化防御。我们将通过以下特定目的来确定BMAL1依赖的ROS稳态调控的分子机制以及生物钟在这一过程中的作用：(A1)研究BMAL1转录靶标PRDX1、PRDX6和SOD1在BMAL1依赖的ROS稳态调控中的作用。(A2)研究昼夜节律蛋白CLOCK和CRY1对BMAL1依赖的ROS稳态调节的影响。(A3)研究BMAL1依赖的ROS体内动态平衡和抗氧化防御。 与公共健康相关：这个项目讨论了生物钟蛋白在防御生物体免受自由基有害行为中的作用。这些结果将有助于了解心脏病、中风和糖尿病等疾病发生的分子基础，并制定合理的治疗和预防策略。

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.