Mammalian circadian rhythms: from genes to mechanisms

哺乳动物昼夜节律：从基因到机制

• 批准号: 10641955
• 负责人: Seung-Hee Yoo
• 金额: $ 38.79万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641955
• 关键词: Behavior; Biochemical; Biological; Biological Clocks; Breeding; Cell physiology; Cells; Chronotherapy; Circadian Rhythms; Complement; Disease; Dissection; Foundations; Generations; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Health; Hypothalamic structure; Image; Knowledge; Mammals; Methodology; MicroRNAs; Molecular; Mus; Muscle function; Myocardium; Nerve Degeneration; Periodicity; Phenotype; Physiological; Physiological Processes; Physiology; Play; Proteins; Public Health; Reagent; Regulation; Reporter; Reporting; Research; Role; Running; Sarcomeres; Scheme; Skeletal Muscle; Striated Muscles; System; Tissues; Variant; age related; circadian; circadian pacemaker; exome sequencing; glycogen synthase kinase 3 beta; insight; interest; mouse genetics; mutant; novel; proteostasis; screening; suprachiasmatic nucleus; ubiquitin-protein ligase

PROJECT SUMMARY / ABSTRACT Circadian clocks play fundamental roles in regulating essential cellular and physiological processes. The mammalian clock is comprised of cell-autonomous oscillators orchestrated by the hypothalamic suprachiasmatic nuclei (SCN) to perform tissue and systemic functions. More than a dozen core components of the oscillator have been identified; however, significant knowledge gaps remain regarding regulatory mechanisms/components and tissue-specific functions in the clock system. My previous research has provided important insights into mammalian circadian rhythms. For example, I generated Per2::Luc reporter mice which proved to be a powerful reagent ubiquitously employed in the clock field. We recently reported a second- generation reporter mouse line, Per2::LucSV, and demonstrated a novel miRNA regulation of PER2 accumulation and a positive role of PER2 in its own transcription. Most relevant to the current MIRA application, I have been interested in combining mouse forward genetic screening and mechanistic studies to probe fundamental clock functions. Previously we reported the identification by mouse screening and mechanistic dissection of two antagonistic E3 ligase, FBXL3 and FBXL21 in circadian period regulation. More recently, we uncovered a GSK-3beta-FBXL21 regulatory cascade controlling rhythmic degradation of the sarcomere protein TCAP and skeletal muscle function. Building on these prior studies, the current proposal aims to determine tissue-specific circadian mechanisms of FBXL21 and to identify novel clock components from a streamlined mouse screening. We will examine new targets and functions of FBXL21 in striated muscles including skeletal and cardiac muscles, focusing on proteostasis and myogenic differentiation. Leveraging expertise in mouse forward genetic screening, I recently performed a genetic screening for dominant phenotypes using an efficient breeding/phenotyping scheme. Whole-exome sequencing and variant analysis pinpointed a novel circadian mutant line with a lengthened circadian wheel-running period and age- dependent neurodegeneration. We will identify this new genetic component of the clock and characterize the underlying regulatory mechanisms. Overall, these studies promise to discover important mechanisms and functions of circadian rhythms in mammals. I have established an integrative research capability combining mouse genetics and phenotyping, biochemical/molecular/cellular studies, imaging methodologies, and omics platforms, complemented by expertise from a broad network of collaborators. These together form an excellent foundation for the proposed research. The ultimate goal is to understand how biological timing governs bodily function and what we can do to safeguard our health by optimizing our natural clock.

项目总结/摘要 生物钟在调节基本的细胞和生理过程中起着重要的作用。的 哺乳动物的生物钟是由细胞自主振荡器组成的， 视交叉上核（SCN）执行组织和系统功能。十多个核心部件 已经确定了振荡器;然而，在监管方面仍然存在重大知识差距 时钟系统中的机制/组件和组织特异性功能。我之前的研究提供了 哺乳动物昼夜节律的重要见解。例如，我产生了Per 2：：Luc报告小鼠， 被证明是时钟领域普遍使用的强大试剂。我们最近报道了第二起- Per 2：：LucSV，并证明了一种新的PER 2的miRNA调控 积累和PER 2在其自身转录中的积极作用。与当前MIRA最相关 应用，我一直有兴趣结合小鼠正向遗传筛选和机制研究， 探针基本时钟功能。以前我们报道了通过小鼠筛选和 两种拮抗性E3连接酶FBXL 3和FBXL 21在昼夜节律调节中的机制剖析。更 最近，我们发现了GSK-3 β-FBXL 21调控级联控制的节律性降解， 肌节蛋白TCAP和骨骼肌功能。在这些先前研究的基础上，目前的建议 旨在确定FBXL 21的组织特异性昼夜节律机制，并确定新的时钟组件 从一个精简的小鼠筛选中。我们将研究FBXL 21在横纹肌中的新靶点和功能， 肌肉，包括骨骼肌和心肌，专注于蛋白质稳态和肌源性分化。 利用小鼠正向遗传筛查的专业知识，我最近进行了一项遗传筛查， 使用有效的育种/表型分析方案确定显性表型。全外显子组测序和变体 分析指出了一种新的昼夜节律突变系，其昼夜节律轮运行周期和年龄延长， 依赖性神经变性我们将确定这个新的遗传组成部分的时钟和特点， 基础监管机制。总的来说，这些研究有望发现重要的机制， 哺乳动物的昼夜节律功能。我已经建立了一个综合研究能力， 小鼠遗传学和表型分析、生物化学/分子/细胞研究、成像方法学和组学 平台，并辅之以广泛的合作者网络的专业知识。这些共同构成了一个优秀的 为拟议的研究奠定基础。最终的目标是了解生物计时如何支配身体 功能和我们可以做些什么来保护我们的健康，通过优化我们的自然时钟。

项目成果

The Polymethoxyflavone Sudachitin Modulates the Circadian Clock and Improves Liver Physiology

多甲氧基黄酮 Sudachitin 调节昼夜节律时钟并改善肝脏生理机能

• DOI: 10.1002/mnfr.202200270
• 发表时间: 2023
• 期刊: Molecular Nutrition & Food Research
• 作者: Mawatari Kazuaki;Koike Nobuya;Nohara Kazunari;Wirianto Marvin;Uebanso Takashi;Shimohata Takaaki;Shikishima Yasuhiro;Miura Hiroyuki;Nii Yoshitaka;Burish Mark J.;Yagita Kazuhiro;Takahashi Akira;Yoo Seung‐Hee;Chen Zheng
• 通讯作者: Chen Zheng