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 哺乳动物依靠生物钟系统来协调日常的系统新陈代谢和生理。在 这个系统，即视交叉上核(SCN)的中央时钟或起搏器，每天都通过光进行同步 并且被认为是对外围的“从属”组织时钟的分级控制。鉴于SCN 时钟对光有反应，外周组织中的时钟在很大程度上受到营养线索的影响(例如，摄食- 禁食)，并且即使当它与基于光的定时相反时，也可以与倒置的进料计划同步 SCN的信号。组织特异性时钟缺陷的小鼠模型进一步表明，两个中枢时钟都在 大脑和外周的局部时钟对于特定组织的完整昼夜节律是必要的， 肝脏中的概念就是例证。因此，生物钟系统看起来是一个联邦网络 相互依赖的组织时钟协同工作，实现生物的动态平衡。尽管我们知道 生物钟之间的这种相互作用是存在的，生物钟通信的机制和 这种串扰在当地整合的监管尚不清楚。这一概念提出了重要的问题。是 外周组织时钟真的是自主的，这意味着它们能在不受其他时钟影响的情况下振荡吗？至 它们的功能在多大程度上依赖于外部节律信号，如定时代谢信号？要回答这些问题 问题是，我们产生的小鼠除了肝脏以外的所有组织中都没有时钟，在肝脏中，时钟 是重组的(重组的[RE]小鼠)。我们的初步数据显示，肝病小鼠的肝钟 在明暗条件下自主振荡，仅重现正常节奏的约10% 转录输出，但在黑暗-黑暗条件下停止振荡。因此，在具体目标1中，我们将 确定肝脏生物钟对光的自主反应，并确定潜在的光反应分子 调解人。在具体目标2中，我们将确定限时喂养、同步器和驱动器 在肝脏的节律性转录中，可以恢复一部分缺失的~90%的正常节律性转录 输出。此外，我们将测试这是否通过NAD+向时钟发出代谢信号来实现。整体而言 这项建议的目标是明确自主肝钟和两个 驱动昼夜节律系统的主要因素是光和食物。在这样做的过程中，我们将揭示 肝脏的生物钟，并开始梳理它与其他生物钟和系统生理的相互作用。给定 生物钟紊乱与代谢性疾病之间的确定关系，以及 光和食物在日常生活中的渗透性，这些发现将提高我们对时钟的理解-- 新陈代谢交叉点，告知人类健康。