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

通过有节律的食物摄入和 mTOR 通路调节昼夜节律生理学

• 批准号: 10579228
• 负责人: Jerome Menet
• 金额: $ 37.09万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-25 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579228
• 关键词: Arrhythmia; Binding; Biochemical; Biochemical Pathway; Biological; Biological Process; Bypass; Cardiovascular Diseases; Cells; Chronotherapy; Circadian Dysregulation; Circadian Rhythms; Complement; Complex; Data; Development; Disease; Drug usage; Eating; Elderly; Exhibits; FRAP1 gene; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Half-Life; Hepatic; Homeostasis; Hour; Human; Impairment; Knock-out; Liver; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Molecular; Mus; Mutation; Pathologic; Pathway interactions; Periodicity; Peripheral; Pharmacological Treatment; Phosphotransferases; Physiology; Publishing; Regulation; Role; Signal Transduction; Sirolimus; Testing; Time; Tissues; Transcriptional Regulation; United States; Wild Type Mouse; circadian pacemaker; circadian regulation; detection of nutrient; experimental study; feeding; glycogenesis; in vivo; lipid biosynthesis; mTOR Inhibitor; mTOR Signaling Pathway; mTOR inhibition; molecular clock; novel; novel strategies; pharmacologic; prevent; restoration; suprachiasmatic nucleus; transcription factor; transcriptome; virtual

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.

项目概要 几乎每个哺乳动物细胞都有一种计时机制，即生物钟，可以驱动明显的节律 基因表达来协调生化和代谢途径的日常活动。符合 生物钟控制的大量生物功能，节律性基因表达的破坏 导致一系列疾病的发展，包括代谢疾病、心血管疾病 疾病和癌症。而且，美国最常用的药物直接针对以下产品： 有节奏地表达的基因。由于这些原因，表征节律基因的机制 表达不仅对于理解时钟功能障碍如何导致病理状况至关重要，而且对于理解时钟功能障碍如何导致病理状况至关重要。 最佳时间药物治疗。节律基因表达被认为主要受 每个哺乳动物细胞中都存在分子生物钟。然而，来自我们实验室的越来越多的证据和 其他人认为，进食节律等环境信号会产生 24 小时的基因表达节律 不涉及生物钟振荡。在初步研究中，我们表明进食的幅度 节律控制小鼠肝脏中 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生物钟，该生物钟继续表现出 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节律 表达依赖于营养感应激酶 mTOR 的节律活性。该提案建立在这些基础上 新的令人兴奋的数据和拟议的实验将确定喂养节律是否调节节律基因 通过以下方式表达：（1）控制 mTOR 信号通路的节律活性，以及​​（2）调节节律性 代谢转录因子的活性。这些实验的结果预计会发现新颖且 哺乳动物节律基因表达调控的重要机制，并提供新的 生物功能如何与环境循环同步并协调的概念框架 组织之间。预计它们还将导致制定新的战略以促进技术进步 时间疗法以及恢复昼夜节律不佳的人类的节律基因表达 比如轮班工人和老人。