Dissecting the autonomy of the liver circadian clock

剖析肝脏生物钟的自主性

• 批准号: 10093971
• 负责人: Kevin B Koronowski
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093971
• 关键词: Affect; Animals; Area; Automobile Driving; Behavior; Biological Clocks; Biology; Brain; Cardiovascular Diseases; Cells; Chronotherapy; Circadian Dysregulation; Circadian Rhythms; Clinical Treatment; Communication; Cues; Darkness; Data; Diabetes Mellitus; Disease; Distal; Environmental Risk Factor; Fasting; Feeding behaviors; Food; Genetic; Genetic Transcription; Goals; Health; Homeostasis; Human; Hypothalamic structure; Indirect Calorimetry; Lesion; Life; Light; Link; Liver; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Neurons; Nutritional; Obesity; Organ; Output; Pacemakers; Periodicity; Peripheral; Physiological; Physiology; Regulation; Signal Transduction; Structure; System; Testing; Time; Time-restricted feeding; Tissue Model; Tissues; Transcript; Work; base; circadian; circadian pacemaker; daily functioning; feeding; feeding schedule; improved; insight; light effects; liver function; molecular clock; mouse model; novel; reconstitution; response; suprachiasmatic nucleus; transcriptome; transcriptomics

Summary/Abstract Mammals rely on the circadian clock system to orchestrate daily systemic metabolism and physiology. Within this system, the central clock or pacemaker in the suprachiasmatic nucleus (SCN) is synchronized daily by light and is considered hierarchically dominant over “subordinate” tissue clocks in the periphery. Whereas the SCN clock is responsive to light, clocks in peripheral tissues are largely influenced by nutritional cues (e.g. feeding- fasting) and can be synchronized to an inverted feeding schedule even when it opposes the light-based timing signals of the SCN. Mouse models of tissue-specific clock deficiency indicate further that both central clocks in the brain and local clocks in the periphery are necessary for full circadian rhythmicity in a particular tissue, a notion exemplified in the liver. Thus, the circadian clock system is a seemingly federated network of interdependent tissue clocks that work in concert to achieve organismal homeostasis. Although we know that this interplay between body clocks exists, the mechanisms through which clocks communicate and the levels of regulation where this cross talk integrates locally are not known. This notion raises important questions. Are peripheral tissue clocks truly autonomous, meaning can they oscillate without influence from other clocks? To what extent does their function depend on extrinsic rhythmic signals like timed metabolic cues? To answer these questions, we have generated mice which are devoid of clocks in all tissues except for the liver, where the clock is reconstituted (Liver-Reconstituted [RE] mice). Our preliminary data show that the liver clock of Liver-RE mice oscillates autonomously under light-dark conditions, recapitulating only ~10% of the normally rhythmic transcriptional output, but ceases to oscillate under dark-dark conditions. Therefore, in Specific Aim 1 we will determine the liver clock's autonomous response to light and identify potential light-responsive molecular mediators. In Specific Aim 2 we will determine whether time-restricted feeding, a synchronizer and driver of rhythmic transcripts in the liver, can reinstate a portion of the missing ~90% of normally rhythmic transcriptional output. Moreover, we will test if this is achieved through metabolic signaling to the clock via NAD+. The overall goal of this proposal is to identify the interactions between specifically the autonomous liver clock and the two main factors that drive the circadian system, light and food. In doing so, we will reveal the intrinsic capacity of the liver clock and begin to tease apart its interactions with other clocks and systemic physiology. Given the established relationship between disruption of the circadian clock and metabolic disease, as well as the pervasiveness of light and food in every day life, these findings will improve our understanding of the clock- metabolism intersection and inform on human health.

摘要/摘要 哺乳动物依靠昼夜节律系统来协调每日系统性的代谢和生理学。之内 该系统，上核（SCN）中的中央时钟或起搏器每天通过光同步 并被认为在外围的“下属”组织时钟上被认为在层次上占主导地位。而SCN 时钟对光的反应敏感，外周组织中的时钟在很大程度上受营养线索的影响（例如，喂养 - 禁食），即使反对基于光的时机，也可以将其同步到倒喂食时间表 SCN的信号。组织特异性时钟缺陷的鼠标模型进一步表明两个中央时钟 外围的大脑和局部时钟对于特定组织中的全昼夜节律是必需的 在肝脏中举例说明了概念。那就是昼夜节律系统是一个看似联合的网络 相互依存的组织时钟协同工作以实现有机稳态。虽然我们知道 身体时钟之间存在这种相互作用，时钟传达的机制以及 在本地集成的该串讨论的调节尚不清楚。这个概念提出了重要的问题。是 外围组织时钟确实是自主的，这意味着它们是否可以振荡而不会受到其他时钟影响？到 它们的功能在多大程度上取决于诸如定时代谢线索之类的外部节奏信号？回答这些 问题，我们已经产生了鼠标，这些小鼠始终没有时钟，除了肝脏 被重构（肝脏回合[RE]小鼠）。我们的初步数据表明肝脏RE小鼠的肝时钟 在浅黑暗条件下自主振荡，仅概括了约10％的正常节奏 转录输出，但在暗黑条件下停止振荡。因此，在特定的目标1中，我们将 确定肝时钟对光的自主反应并识别潜在的光反应分子 调解人。在特定目标2中，我们将确定是否限制时间喂养，同步器和驱动程序 肝脏中的节奏转录本可以恢复缺失的一部分〜90％的正常节奏转录 输出。此外，我们将通过NAD+向时钟的代谢信号传导来测试这是否实现。总体 该建议的目标是确定特定自主肝时钟与两个之间的相互作用 推动昼夜节律系统，轻便和食物的主要因素。这样，我们将揭示 肝时钟，开始嘲笑其与其他时钟和系统生理学的相互作用。鉴于 昼夜节律中断与代谢疾病的破坏之间的建立关系以及 在日常生活中光和食物普遍存在，这些发现将提高我们对时钟的理解 - 代谢交集并告知人类健康。