Ultradian to circadian transcriptome re-wiring underlies liver aging

超昼夜节律转录组重新布线是肝脏衰老的基础

• 批准号: 10701666
• 负责人: Bokai Zhu
• 金额: $ 23.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701666
• 关键词: Acceleration; Aging; Animals; Behavior; Behavioral; Biogenesis; Biological Rhythm; Bioperiodicity; Caenorhabditis elegans; Caloric Restriction; Cells; Circadian Dysregulation; Circadian Rhythms; Cues; Data; Deterioration; Disease; Endoplasmic Reticulum; Exhibits; Female; Gender; Gene Expression; Genes; Genetic; Glycerolipid Metabolism Pathway; Golgi Apparatus; Health; Hepatic; Homeostasis; Hour; Human; Impairment; Intervention; Jet Lag Syndrome; Label; Life; Link; Liver; Malignant Neoplasms; Mammals; Metabolic; Metabolic syndrome; Metabolism; Molecular; Mus; Nematoda; Organ; Organ Model; Organism; Papio; Pathway interactions; Phenotype; Physiological; Physiology; Process; Proteins; Quality Control; RNA Splicing; Reporting; Research; Ribosomes; Sorting; Sphingolipids; Testing; Time-restricted feeding; Translational Regulation; Work; XBP1 gene; circadian; circadian pacemaker; circadian transcriptome; experimental study; healthspan; immune function; improved; in vivo; innate immune function; lipid metabolism; male; marine; middle age; mouse model; novel; novel therapeutics; prevent; protein degradation; protein folding; response; secretory protein; shift work; transcription factor; transcriptome; transcriptome sequencing; young adult

Project Summary/Abstract In addition to the circadian rhythms (~24h oscillation), ultradian rhythms (with period smaller than 24h) also exist, among which 12h rhythms were prevalently found in multiple species ranging from circatidal marine animals, to nematode C. elegans and mammals like mouse, baboon and even humans. Our group recently discovered a mammalian 12h-clock that is evolutionarily conserved, cell-autonomous and established independently from the circadian clock but dependent on the unfolded protein response transcription factor XBP1s. Liver-specific deletion of XBP1s globally impairs the murine 12h transcriptome, but not circadian rhythms in vivo. XBP1s- dependent hepatic 12h transcriptome preferentially peaks at dawn and dusk, and is remarkably enriched in pathways regulating innate immune functions and endoplasmic reticulum (ER) and the Golgi apparatus homeostasis, including translation regulation, protein processing and sorting in ER and Golgi, protein quality control and sphingolipid and glycerolipid metabolism. These pathways are often dysregulated during aging and aging-related diseases. While it has been recently established that the 24h circadian rhythms undergo prevalent reprogramming during aging, whether the 12h-clock dysregulation is also causally linked to aging and/or aging- related diseases remains ill defined. Very intriguingly, preliminary data revealed a very robust global reprogramming of 12h-cycling transcriptome to 24h circadian rhythms during aging in mouse liver, which is further associated with a conversion of 12h hepatic XBP1s oscillation to 24h circadian oscillation. Based upon these findings, we hypothesize that 12h-to-24h (circadian) reprogramming can accelerate liver aging. We will generate mouse models of hepatic 12h-to-24h reprogramming. Extensive phenotyping experiments will be performed to determine if genetically-induced 12h-to-24h reprogramming is sufficient to drive hepatic aging in mice. We will further perform temporal RNA-Seq and hepatic secretome profiling to identify the molecular mechanism underlying this reprogramming. This work will therefore establish 12h-clock dysregulation as a novel hallmark of aging and suggest that new therapeutics aimed at preventing this 12h-to-24h reprogramming could be effective at improving health span in humans.

项目概要/摘要 除了昼夜节律（~24小时振荡）外，还存在超昼夜节律（周期小于24小时）， 其中 12 小时节律普遍存在于多种物种中，从昼夜节律海洋动物到 线虫、秀丽隐杆线虫和哺乳动物，如小鼠、狒狒，甚至人类。我们小组最近发现了一个 哺乳动物的 12 小时时钟在进化上是保守的、细胞自主的并且独立于 生物钟，但依赖于未折叠蛋白反应转录因子 XBP1s。肝脏特异性 XBP1 的缺失会整体损害小鼠 12 小时转录组，但不会损害体内的昼夜节律。 XBP1s- 依赖肝12小时转录组优先在黎明和黄昏达到峰值，并且显着富集 调节先天免疫功能、内质网 (ER) 和高尔基体的途径 稳态，包括翻译调节、内质网和高尔基体中的蛋白质加工和分类、蛋白质质量 控制鞘脂和甘油脂代谢。这些通路在衰老过程中经常失调 与衰老相关的疾病。虽然最近已确定 24 小时昼夜节律普遍存在 衰老过程中的重编程，12小时时钟失调是否也与衰老和/或衰老有因果关系 相关疾病仍不明确。非常有趣的是，初步数据显示全球经济非常强劲 小鼠肝脏衰老过程中 12 小时循环转录组重编程为 24 小时昼夜节律， 进一步与 12 小时肝脏 XBP1s 振荡到 24 小时昼夜节律振荡的转换相关。基于 根据这些发现，我们假设 12 小时至 24 小时（昼夜节律）重新编程可以加速肝脏衰老。我们将 生成肝脏 12 小时至 24 小时重编程的小鼠模型。广泛的表型实验将 旨在确定基因诱导的 12 小时至 24 小时重编程是否足以驱动肝脏衰老 老鼠。我们将进一步进行时间 RNA 测序和肝分泌蛋白组分析来鉴定分子 这种重新编程的机制。因此，这项工作将把 12 小时时钟失调确立为一部小说 衰老的标志，并表明旨在阻止这种 12 小时至 24 小时重编程的新疗法可以 有效延长人类的健康寿命。