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全身代谢和生理机能。 在这个系统中，视交叉上核（SCN）的中央时钟或起搏器每天通过光进行同步 并且被认为在外周的“从属”组织时钟中处于等级主导地位（SCN 除外）。 生物钟对光敏感，外周组织的生物钟在很大程度上受到营养因素的影响（例如进食） 禁食），并且可以同步到反向喂养计划，即使它与基于光的时间相反 组织特异性时钟缺陷的小鼠模型的信号进一步表明，两个中央时钟都处于 大脑和周围的本地时钟对于特定组织的完整昼夜节律是必要的， 因此，生物钟系统是一个看似联合的网络。 相互依赖的组织时钟协同工作以实现生物稳态。 生物钟之间存在这种相互作用，生物钟沟通的机制以及生物钟的水平 这种串扰在本地整合的规则尚不清楚。 外围组织时钟真正自主，这意味着它们可以在不受其他时钟影响的情况下振荡吗？ 它们的功能在多大程度上依赖于定时代谢线索等外在节律信号？ 问题是，我们培育出了除肝脏以外所有组织中都没有时钟的小鼠，肝脏中的时钟 我们的初步数据显示肝脏重建小鼠的肝脏时钟。 在明暗条件下自主振荡，仅重演正常节律的 10% 转录输出，但在暗-暗条件下停止振荡，因此，在特定目标 1 中，我们将。 确定肝脏时钟对光的自主反应并识别潜在的光响应分子 在具体目标 2 中，我们将确定是否有时间限制的喂食、同步器和驱动器。 肝脏中的节律性转录本，可以恢复部分缺失的约 90% 的正常节律性转录本 此外，我们将测试这是否是通过 NAD+ 向时钟发出代谢信号来实现的。 该提案的目标是确定自主肝脏时钟与两者之间的相互作用 驱动昼夜节律系统的主要因素是光和食物，在此过程中，我们将揭示昼夜节律系统的内在能力。 肝脏时钟并开始梳理其与其他时钟和全身生理学的相互作用。 确定了生物钟紊乱与代谢疾病之间的关系，以及 光和食物在日常生活中无处不在，这些发现将提高我们对时钟的理解 新陈代谢交叉点并为人类健康提供信息。