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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

基本信息

批准号：
10367363
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
项目类别：
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/10367363
关键词：
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 Lead Liver Malignant Neoplasms Mammalian Cell Mammals Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolism Molecular Mus Mutation Pathologic Pathway interactions Periodicity Peripheral Pharmacological Treatment Pharmacology Phosphotransferases Physiology Publishing Regulation Role Signal Transduction Sirolimus Testing Time Tissues Transcriptional Regulation United States Wild Type Mouse base 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 prevent restoration suprachiasmatic nucleus transcription factor transcriptome virtual

项目摘要

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.

项目总结