Circadian clock and dietary restriction

昼夜节律时钟和饮食限制

• 批准号: 8193927
• 负责人: Roman V Kondratov
• 金额: $ 29.11万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193927
• 关键词: Address; Adenosine Monophosphate; Affect; Age; Aging; Aging-Related Process; Agreement; Animals; BMAL1 protein; Behavior; Brain; Cells; Circadian Rhythms; Clock protein; Complex; Data; Development; Diabetes Mellitus; Disease; Environment; Feedback; Glucose; Heart Diseases; Hour; Human; In Vitro; Intake; Intervention; Invertebrates; Life; Liver; Longevity; Malignant Neoplasms; Mammals; Mediating; Metabolism; Molecular; Mus; Muscle; Nutrient; Organism; Osteoporosis; Pathology; Pathway interactions; Phosphorylation; Physiological; Physiology; Plasma; Post-Translational Protein Processing; Premature aging syndrome; Prevention; Protein Kinase; Proteins; Regulation; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Staging; Stress; System; Therapeutic; Time; Tissues; Transcription Coactivator; Transcription Repressor/Corepressor; Up-Regulation; Wild Type Mouse; Yeasts; base; circadian pacemaker; dietary restriction; fly; human FRAP1 protein; in vivo; innovation; mimetics; mutant; novel; therapy development; treatment strategy

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.

描述（由申请人提供）：饮食限制（DR）是一种强有力的干预措施，它可以减缓衰老过程并延长从酵母到哺乳动物等生物体的寿命。 TOR 信号通路是一条进化上保守的通路，与衰老的控制有关，TOR 是 DR 发挥全部作用所必需的。 Hi95 /sestrin2 是哺乳动物和无脊椎动物中 TOR 通路的负调节因子。我们发现，BMAL1缺陷小鼠的大脑、肌肉和肝脏中Hi95/sestrin2表达显着降低，而CRY缺陷小鼠的相同组织中Hi95/sestrin2表达显着增加；此外，BMAL1 缺陷会导致 TOR 信号传导上调，表明 BMAL1 是 TOR 通路的负调节因子。 BMAL1 和 CRY 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设： 目标 1. 研究葡萄糖调节 BMAL1 转录活性的分子机制。目的 2. 研究生物钟蛋白在 Hi95-mTOR 通路调节中的作用。目标 3. 研究生物钟和生物钟蛋白 BMAL1 和 CRY 在饮食限制中的作用。 公共健康相关性：该项目探讨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，已被证明可以延长包括人类在内的多种生物体的寿命。这项研究获得的数据将有助于了解衰老和与年龄相关的疾病的分子基础，并制定治疗和预防心脏病、癌症、糖尿病和骨质疏松症等与年龄相关的疾病的生理和药理学策略。