Mammalian target of rapamycin signaling and the suprachiasmatic circadian clock

雷帕霉素信号传导和视交叉上生物钟的哺乳动物靶标

• 批准号: 10409838
• 负责人: Ruifeng (Ray) Cao
• 金额: $ 35.6万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409838
• 关键词: Actins; Address; Animals; Behavior; Behavioral; Behavioral Assay; Biological Assay; Biological Clocks; Bioluminescence; Brain; Brain Diseases; Cell Nucleus; Circadian Dysregulation; Clinical; Complex; Cytoskeleton; Data; EIF4EBP1 gene; Environment; Event; Exhibits; Exposure to; FDA approved; FRAP1 gene; Gene Expression; Genetic; Genetic Models; Genetic Translation; Goals; Hypothalamic structure; Knowledge; Light; Mammals; Mediating; Mental disorders; Messenger RNA; Metabolism; Molecular; Mus; Mutant Strains Mice; Organism; Pathogenesis; Patients; Periodicity; Pharmaceutical Preparations; Pharmacology; Phase; Photoperiod; Physiological; Physiology; Property; Protein Biosynthesis; Proteins; Publishing; Raptors; Regulation; Repression; Research; Ribosomal Protein S6 Kinase; Role; Running; Signal Pathway; Signal Transduction; Sleep Disorders; Sleep disturbances; Sleeplessness; Slice; Testing; Therapeutic Effect; Time; Tissues; Translations; Western Blotting; Work; base; circadian; circadian pacemaker; conditional knockout; environmental change; extracellular; genome-wide; inhibitor; innovation; interdisciplinary approach; loss of function; mTORopathies; microscopic imaging; mouse genetics; nervous system disorder; next generation; novel; photoperiodicity; polymerization; protein complex; rational design; response; suprachiasmatic nucleus

Project Summary The objective of the proposed research is to understand physiological functions of the mammalian target of rapamycin (mTOR) signaling pathway in the brain circadian (~24 h) clock, the hypothalamic suprachiasmatic nucleus (SCN). To be synchronized with the external and internal environment, gene expression in the SCN clock is regulated by an intracellular signaling network. A major gap exists in our understanding of the key signaling events that couple extracellular and intracellular signals to regulate protein synthesis (mRNA translation). mTOR is a master regulator of mRNA translation. It forms two functionally distinct branches, mTORC (mTOR complex) 1 and mTORC2. Based on our published work and unpublished preliminary data, our overall hypothesis is that mTORC1 controls mRNA translation and SCN cell synchrony, whereas mTORC2 controls circadian cytoskeleton reorganization, both of which are critical for the SCN clock function. To test the hypothesis, activities of specific mTOR components will be manipulated by genetic and pharmacological approaches. The circadian clock functions will be assessed at the molecular, cellular and animal behavioral levels using a multidisciplinary approach. Aim 1 will define the functions of the mTORC1 translation effectors S6Ks in the SCN. We hypothesize that S6Ks regulate the photic clock resetting by regulating mRNA translation. Aim 2 will assess a role for mTORC1 in mediating photoperiodic regulation of SCN cell synchrony. We hypothesize that mTORC1 mediates the regulation of SCN synchrony by photoperiods. Aim 3 will identify a role for mTORC2 in the circadian clock. We hypothesize that mTORC2 regulates SCN properties by controlling circadian cytoskeleton reorganization. The proposed work is innovative because it utilizes our latest mouse genetic models to address conceptually novel questions regarding the role of mTOR in the brain clock. The contributions of the proposed work are expected to be significant, because it will elucidate fundamental mechanisms whereby mTOR regulates the function of the circadian clock. Aberrant mTOR activities in the brain are identified in neurological and psychiatric diseases, which are often accompanied by disrupted daily rhythms in patients. FDA-approved mTOR inhibitors can cause sleep problems. The proposed research will generate new knowledge that is essential for a mechanistic understanding of the clinical issues regarding mTOR and clock/sleep disruptions.

项目摘要 拟议研究的目的是了解哺乳动物靶标的生理功能 雷帕霉素（MTOR）信号传导途径在脑昼夜节律（〜24小时）时钟，下丘脑上张力 核（SCN）。要与外部和内部环境同步，SCN中的基因表达 时钟由细胞内信号网络调节。我们对钥匙的理解存在一个主要差距 信号事件，将细胞外和细胞内信号融合以调节蛋白质合成（mRNA） 翻译）。 MTOR是mRNA翻译的主要调节剂。它形成了两个在功能上不同的分支，mtorc （MTOR复合物）1和MTORC2。根据我们已发表的工作和未发表的初步数据，我们的总体 假设MTORC1控制mRNA翻译和SCN细胞同步，而MTORC2 控制昼夜节律细胞骨架重组，这两个对SCN时钟功能至关重要。到 测试假设，特定MTOR成分的活性将由遗传和药理操纵 方法。昼夜节律函数将在分子，细胞和动物行为上进行评估 使用多学科方法的水平。 AIM 1将定义MTORC1翻译效应子的功能 S6K在SCN中。我们假设S6K通过调节mRNA翻译来调节光钟重置。 AIM 2将评估MTORC1在介导SCN细胞同步光周期调控中的作用。我们 假设MTORC1通过光周期介导SCN同步的调节。 AIM 3将确定角色 对于昼夜节律中的mtorc2。我们假设MTORC2通过控制 昼夜节律重组。拟议的工作具有创新性，因为它利用了我们的最新鼠标 遗传模型解决了有关MTOR在大脑时钟中的作用的概念新问题。这 拟议工作的贡献预计将是重要的，因为它将阐明基本 MTOR调节昼夜节律功能的机制。大脑中的异常活动 在神经系统和精神病中鉴定出来，通常伴随着每日障碍 在患者中。 FDA批准的MTOR抑制剂可能会导致睡眠问题。拟议的研究将产生 对MTOR和MTOR的临床问题的机械理解至关重要的新知识 时钟/睡眠中断。