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 Based on our published work and unpublished preliminary data, our overall hypothesis is that mTORC1 controls mRNA translation and SCN cell synchrony, whereas mTORC2 controls circadian cytoskeleton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 这项拟议的研究的目的是了解哺乳动物靶标的生理功能。 雷帕霉素(MTOR)信号通路在大脑昼夜节律(~24小时)时钟、下丘脑视交叉上核中的作用 核(SCN)。要与外部和内部环境同步，基因在SCN中的表达 时钟由细胞内信令网络调节。我们对关键的理解存在着很大的差距 连接细胞外和细胞内信号以调节蛋白质合成(MRNA)的信号事件 译文)。MTOR是信使核糖核酸翻译的主要调节者。它形成了两个功能截然不同的分支，mTORC (mTOR复合体)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控制着mRNA的翻译和SCN细胞的同步性，而mTORC2 控制昼夜节律的细胞骨架重组，这两者对SCN时钟功能都是至关重要的。至 检验假设，特定mTOR组分的活动将受到遗传和药理学的控制 接近了。生物钟的功能将从分子、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。我们推测S6K可能通过调节mRNA的翻译来调节光钟的重置。 目的2将评估mTORC1在介导SCN细胞同步性的光周期调节中的作用。我们 假设mTORC1介导了光周期对SCN同步性的调节。目标3将确定一个角色 对于生物钟中的mTORC2。我们假设mTORC2通过控制SCN属性来调节SCN属性 昼夜节律的细胞骨架重组。提议的工作是创新的，因为它利用了我们最新的鼠标 基因模型，以解决有关mTOR在大脑时钟中的作用的概念上的新问题。这个 预计拟议工作的贡献将是巨大的，因为它将阐明根本 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，这些疾病通常伴随着日常节律的中断 在病人身上。FDA批准的mTOR抑制剂会导致睡眠问题。拟议的研究将产生 新知识对于机械地理解有关mTOR和 时钟/睡眠中断。