Mammalian target of rapamycin signaling and the suprachiamatic 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

基本信息

批准号：
10930427
负责人：
Ruifeng (Ray) Cao
金额：
$ 36.29万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10930427
关键词：
Mammalian target rapamycin signaling suprachiamatic

项目摘要

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 Based on our published work and unpublished preliminary data, our overall hypothesis is that mTORC1 controls mRNA translation and SCN cell synchrony, whereas mTORC2 controls circadian cytoskeleton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。