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

项目总结 几乎每个哺乳动物细胞都有一种计时机制，即生物钟，它驱动着公开的节奏 在基因表达中协调生化和代谢途径的日常活动。与 生物钟控制的大量生物功能，打乱有节奏的基因表达 导致一系列疾病的发展，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是 有节奏地表达的基因。出于这些原因，表征节律基因的潜在机制 表达不仅对理解生物钟功能障碍如何导致病理状况至关重要，而且对 药物治疗的最佳时机。有节律性的基因表达被认为主要受 存在于每个哺乳动物细胞中的分子生物钟。然而，越来越多来自我们实验室的证据和 其他人则认为，摄食节律等环境信号会在基因表达中产生24小时节律 而不涉及昼夜节律的时钟振荡。在初步研究中，我们发现摄食的幅度 节律控制着2000多个基因在小鼠肝脏中的节律表达。令人惊讶的是，这一效应对 基因表达似乎并不直接与肝脏生物钟有关，后者继续表现出 核心时钟基因表达的正常振荡。相反，我们的初步数据表明，基因的节律 它的表达依赖于营养敏感蛋白激酶mTOR的节律性活动。这项建议是建立在这些基础上的 新的令人兴奋的数据和拟议的实验将确定摄食节律是否调节节律基因 通过(1)控制mTOR信号通路的节律性活动和(2)调节节律性 代谢转录因子的活性。这些实验的结果有望发现新的和 调节哺乳动物节律性基因表达的重要机制，并提供新的 生物功能如何与环境周期同步和协调的概念框架 在纸巾之间。预计它们还将导致开发新的战略，以促进 时间疗法和恢复昼夜节律不良的人的节律性基因表达 比如轮班工人和老人。

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.