Regulation of circadian physiology by rhythmic food intake and the mTOR pathway

项目摘要 几乎每一个哺乳动物细胞都有一个计时机制，即生物钟，它驱动着明显的节奏 在基因表达中协调生物化学和代谢途径的日常活动。符合 大量生物功能受生物钟控制，节律基因表达中断 导致包括代谢性疾病、心血管疾病、 疾病和癌症。此外，美国最常用的药物直接针对的产品， 有节奏地表达基因。由于这些原因，表征节律基因的机制 表达不仅对于理解生物钟功能障碍如何导致病理状态至关重要，而且对于理解生物钟功能障碍如何导致病理状态至关重要。 最佳的药物治疗时间。节律性基因表达被认为主要受 在每个哺乳动物细胞中发现的分子生物钟。然而，越来越多的证据，从我们的实验室和 其他人认为，环境信号，如进食节奏，在基因表达中产生24小时的节奏。 而不涉及生物钟振荡。在初步研究中，我们表明， Rhythms控制小鼠肝脏中2000多个基因的节律表达。令人惊讶的是，这种影响 基因表达似乎并不直接涉及肝脏的昼夜节律钟，它继续表现出 核心时钟基因表达的正常波动。相反，我们的初步数据表明， 表达依赖于营养敏感激酶mTOR的节律性活性。这项建议建立在这些 新的令人兴奋的数据和拟议的实验将确定是否喂养节奏调节节奏基因 通过（1）控制mTOR信号通路的节律性活动，和（2）调节mTOR信号通路的节律性活动， 代谢转录因子的活性。这些实验的结果有望揭示新的和 哺乳动物节律性基因表达调控的重要机制，并提供一个新的 生物功能如何与环境周期同步和协调的概念框架 组织之间的联系。预计它们还将导致制定新的战略，以促进 时间疗法和用于恢复表现出不良昼夜节律的人的节律基因表达 比如倒班工人和老人

PROJECT SUMMARY Nearly every mammalian cell harbors a timekeeping mechanism, the circadian clock, that drives overt rhythms in gene expression to coordinate the daily activity of biochemical and metabolic pathways. Consistent with the large number of biological functions controlled by the circadian clock, disruption of rhythmic gene expression leads to the development of a wide range of disorders that include metabolic diseases, cardiovascular disorders and cancer. Moreover, most commonly used drugs in the United States directly target the products of rhythmically expressed genes. For these reasons, characterizing the mechanisms underlying rhythmic gene expression is critical to not only understand how clock dysfunction leads to pathological conditions, but also to optimally time pharmacological treatment. Rhythmic gene expression is thought to be primarily regulated by the molecular circadian clock found in every mammalian cell. However, increasing evidences from our lab and others suggest that environmental signals like feeding rhythms generate 24-hour rhythms in gene expression without involving the circadian clock oscillation. In Preliminary Studies, we show that the amplitude of feeding rhythms controls the rhythmic expression of more than 2000 genes in mouse liver. Surprisingly, this effect on gene expression does not seem to directly involve the hepatic circadian clock, which continues to exhibit normal oscillations in core clock gene expression. Rather, our preliminary data suggest that rhythms in gene expression rely on the rhythmic activity of the nutrient-sensing kinase mTOR. This proposal builds upon these new exciting data and the proposed experiments will determine if feeding rhythms regulate rhythmic gene expression by (1) controlling the rhythmic activity of mTOR signaling pathway, and (2) regulating the rhythmic activity of metabolic transcription factors. Results from these experiments are expected to uncover novel and important mechanisms for the regulation of rhythmic gene expression in mammals, and to provide a new conceptual framework for how biological functions are synchronized to environmental cycles and coordinated between tissues. They are also anticipated to lead to the development of novel strategies for advancements in chronotherapy and for the restoration of rhythmic gene expression in humans showing poor circadian rhythms like shift-workers and elders.