Circadian clock and dietary restriction

描述(申请人提供)：饮食限制(DR)是一种强有力的干预措施，可以减缓衰老过程，延长从酵母到哺乳动物的生物体的寿命。在哺乳动物和无脊椎动物中，TOR信号通路是一条进化保守的通路，参与控制衰老，而TOR是充分发挥其作用所必需的。Hi95/sestrin2是TOR通路的负调控因子。我们发现，在BMAL1缺陷小鼠的脑、肌肉和肝脏中，Hi95/sestrin2的表达显著降低，而在CRY缺陷小鼠的相同组织中表达增加；此外，BMAL1缺陷导致TOR信号的上调，表明BMAL1是TOR途径的负调控因子。BMal1和Crys是生物钟系统的组成部分。因此，我们的初步数据表明，TOR信号通路和生物钟之间存在以前未知的相互作用，这可能解释了生物钟在衰老中的作用。我们假设DR调节生物钟蛋白BMAL1和CRYS的活性，这些蛋白通过调节TOR通路介导DR对长寿的影响。我们将通过以下具体目标来解决这一假说：目的1.研究葡萄糖调节BMAL1转录活性的分子机制。目的2.探讨生物钟蛋白在调节Hi95-mTOR通路中的作用。目的3.研究生物钟和生物钟蛋白BMAL1和CRYS在饮食限制中的作用。 公共卫生相关性：这个项目解决了生物钟在饮食限制中的作用。饮食限制是一种强有力的干预措施，被证明可以延长包括人类在内的各种生物体的寿命。这项研究的结果将有助于了解衰老和年龄相关疾病的分子基础，并制定治疗和预防与年龄相关的疾病如心脏病、癌症、糖尿病和骨质疏松症的生理学和药理学策略。

DESCRIPTION (provided by applicant): Dietary restriction (DR) is a powerful intervention, which slows the aging process and increases the lifespan of organisms, from yeast to mammals. The TOR signaling pathway is an evolutionarily conserved pathway implicated in the control of aging, and TOR is necessary for the full effect of DR. Hi95 /sestrin2 is a negative regulator of TOR pathways in mammals and invertebrates. We have found that Hi95/sestrin2 expression is significantly reduced in the brain, muscles and liver of BMAL1-deficient mice, and is increased in the same tissues of CRY-deficient mice; furthermore, BMAL1 deficiency results in up regulation of TOR signaling, suggesting that BMAL1 is a negative regulator of the TOR pathway. BMAL1 and CRYs are components of the circadian clock system. Thus, our preliminary data suggest a previously unknown interaction between the TOR signaling pathway and the circadian clock which may explain the role of the circadian clock in aging. We hypothesize that DR regulates the activity of the circadian clock proteins BMAL1 and CRYs, and these proteins mediate the effect of DR on longevity through the regulation of TOR pathways. We will address this hypothesis through the following Specific Aims: Aim 1. To study the molecular mechanisms of regulation of BMAL1 transcriptional activity by glucose. Aim 2. To investigate the role of the circadian clock proteins in the regulation of the Hi95-mTOR pathway. Aim 3. To study the role of the circadian clock and circadian clock proteins BMAL1 and CRYs in dietary restriction. PUBLIC HEALTH RELEVANCE: This project addresses the role of the circadian clock in dietary restriction. Dietary restriction is a powerful intervention demonstrated to increase longevity in a variety of organisms, including humans. Data obtained as a result of this study will help to understand the molecular basis of aging and age-associated diseases, and to develop physiological and pharmacological strategies for the treatment and prevention of such age-associated pathologies as heart diseases, cancer, diabetes and osteoporosis.