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: 10030731
• 负责人: Ruifeng (Ray) Cao
• 金额: $ 35.38万
• 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/10030731
• 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; design; environmental change; extracellular; genome-wide; inhibitor/antagonist; innovation; interdisciplinary approach; loss of function; microscopic imaging; mouse genetics; nervous system disorder; next generation; novel; photoperiodicity; polymerization; protein complex; 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 Based on our published work and unpublished preliminary data, our overall hypothesis is that mTORC1 controls mRNA translation and SCN cell synchrony, whereas mTORC2 controls circadian cytoskeleton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.

项目概要 拟议研究的目的是了解哺乳动物目标的生理功能 大脑昼夜节律（~24小时）时钟、下丘脑视交叉上的雷帕霉素（mTOR）信号通路 核（SCN）。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。我们对关键的理解存在重大差距 耦合细胞外和细胞内信号以调节蛋白质合成（mRNA 翻译）。 mTOR 是 mRNA 翻译的主要调节因子。它形成两个功能不同的分支，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，两者对于 SCN 时钟功能都至关重要。到 检验假设，特定 mTOR 成分的活性将受到遗传和药理学的操纵 接近。生物钟功能将从分子、细胞和动物行为方面进行评估 使用多学科方法的水平。目标 1 将定义 mTORC1 翻译效应器的功能 SCN 中的 S6K。我们假设 S6Ks 通过调节 mRNA 翻译来调节光时钟重置。 目标 2 将评估 mTORC1 在介导 SCN 细胞同步光周期调节中的作用。我们 假设 mTORC1 通过光周期介导 SCN 同步调节。目标 3 将确定角色 生物钟中的 mTORC2。我们假设 mTORC2 通过控制来调节 SCN 特性 昼夜节律细胞骨架重组。拟议的工作具有创新性，因为它使用了我们最新的鼠标 遗传模型来解决有关 mTOR 在脑时钟中的作用的概念上的新问题。这 拟议工作的贡献预计将是巨大的，因为它将阐明基本原理 mTOR 调节生物钟功能的机制。大脑中异常的 mTOR 活动 常见于神经和精神疾病，这些疾病通常伴随着日常节律紊乱 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 新知识对于机械理解有关 mTOR 的临床问题至关重要 时钟/睡眠中断。