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.

项目摘要 几乎每个哺乳动物的细胞都有一个计时机制，即昼夜节律，它驱动了明显的节奏 在基因表达中以协调生化和代谢途径的每日活性。与 昼夜节律控制的大量生物学功能，节奏基因表达的破坏 导致各种疾病的发展，包括代谢疾病，心血管疾病 疾病和癌症。此外，美国最常用的药物直接针对 节奏表达的基因。由于这些原因，表征有节奏基因的机制 表达对于不仅了解时钟功能障碍如何导致病理状况至关重要，而且对 最佳时间药理治疗。有节奏的基因表达被认为主要由 在每个哺乳动物细胞中发现的分子昼夜节律时钟。但是，我们实验室的证据增加了 其他人则认为，诸如喂食节奏之类的环境信号在基因表达中产生24小时的节奏 不涉及昼夜节律振荡。在初步研究中，我们表明喂养的幅度 节奏控制了小鼠肝脏中2000多个基因的节奏表达。令人惊讶的是，这种影响 基因表达似乎并不直接涉及肝脏昼夜节律，该时钟继续表现出来 核心时钟基因表达中的正常振荡。相反，我们的初步数据表明基因的节奏 表达依赖于营养感应激酶MTOR的节奏活性。该提议建立在这些基础上 新的令人兴奋的数据和提出的实验将确定喂养节奏是否调节节奏基因 通过（1）控制MTOR信号通路的节奏活性，以及​​（2）调节节奏 代谢转录因子的活性。这些实验的结果预计将发现新颖，并且 调节哺乳动物节奏基因表达的重要机制，并提供新的 生物功能如何同步与环境周期并协调的概念框架 在组织之间。他们还被预计会导致发展新颖策略的发展 年代疗法和恢复人类节奏基因表达 像班次工作者和长者一样。