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 Based on our published work and unpublished preliminary data, our overall hypothesis is that mTORC1 controls mRNA translation and SCN cell synchrony, whereas mTORC2 controls circadian cytoskeleton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点的生理功能， 雷帕霉素（mTOR）信号通路在大脑昼夜（~24小时）时钟，下丘脑视交叉上 核（SCN）。为了与外部和内部环境同步，SCN中的基因表达 生物钟由细胞内信号网络调节。在我们对这把钥匙的理解上存在着一个重大的差距， 耦合细胞外和细胞内信号以调节蛋白质合成（mRNA）的信号传导事件 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mTORC 2。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mTORC 1控制mRNA翻译和SCN细胞同步性，而mTORC 2 控制昼夜节律的细胞骨架重组，这两者对于SCN时钟功能都是至关重要的。到 为了验证这一假设，特定mTOR组分的活性将被遗传和药理学操纵。 接近。生物钟功能将在分子、细胞和动物行为学方面进行评估 采用多学科方法。目标1将定义mTORC 1翻译效应器的功能 SCN中的S6 K。我们推测S6 Ks通过调节mRNA的翻译来调节光钟的重置。 目的2将评估mTORC 1在介导SCN细胞同步性的光周期调节中的作用。我们 假设mTORC 1通过光周期介导SCN同步性的调节。目标3将确定一个角色 mTORC 2在生物钟中的作用我们假设mTORC 2通过控制SCN的性质来调节SCN的性质。 昼夜节律细胞骨架重组。拟议的工作是创新的，因为它利用了我们最新的鼠标 遗传模型来解决有关mTOR在大脑时钟中的作用的概念性新问题。的 预计拟议工作的贡献将是重大的，因为它将阐明基本的 mTOR调节生物钟功能的机制。大脑中异常的mTOR活动 在神经和精神疾病中被发现，这些疾病通常伴有日常节律紊乱 在病人身上。FDA批准的mTOR抑制剂可能导致睡眠问题。这项研究将产生 新的知识，这是必不可少的机械理解有关mTOR的临床问题， 时钟/睡眠中断。