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Project 3: Coactivator-dependent hepatic 12h clock coordinates metabolic and stress rhythms

项目 3：共激活剂依赖性肝脏 12 小时时钟协调代谢和应激节律

基本信息

批准号：
10421284
负责人：
BERT W O'MALLEY
金额：
$ 35.66万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421284
关键词：
ARNTL gene Ablation Adipose tissue Aging Animals Architecture Behavioral Binding Bioenergetics Biological Rhythm Bioperiodicity Body Temperature Cells Cellular Metabolic Process ChIP-seq Chemicals Chromatin Chronic Circadian Rhythms Clinical Colon Cues Data Development Disease Endoplasmic Reticulum Ensure Exhibits Fatty Liver Gene Cluster Gene Expression Genes Genetic Transcription Heart Hepatic High Fat Diet Homeostasis Hormones Hour Human Hypothalamic structure In Vitro Jet Lag Syndrome Kidney Life Light Liver Lung Maintenance Malignant Neoplasms Mediator of activation protein Medical Metabolic Metabolic stress Metabolic syndrome Metabolism Mitochondria Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Nutritional Obesity Organ Model Output Pathology Pathway interactions Periodicity Peripheral Physiological Physiology Planet Earth Prevalence Process Proteins Publishing RNA Splicing Research Role Running Series System Testing Time Tissues Transcriptional Regulation Work XBP1 gene base circadian circadian pacemaker cognitive performance endoplasmic reticulum stress epidemiology study fatty liver disease gene network in vivo liver metabolism mathematical methods mathematical model metabolomics molecular clock mouse model non-alcoholic fatty liver disease novel prevent programs response shift work sleep pattern transcription factor transcriptome sequencing

项目摘要

Project 3 - Project Summary In addition to the well-studied circadian rhythm, a cluster of genes that cycle at the second (12h period) harmonic of circadian rhythmicity was discovered in several peripheral mouse tissues in vivo. Genes exhibiting apparent 12h rhythmicity were enriched in endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways, which are universally conserved adaptive responses to cope with accumulation of unfolded protein in the ER. Despite these initial findings, the exact prevalence of the 12h rhythm in vivo, its relationship with the circadian clock, how the 12h rhythm is established at the molecular level and its precise roles in regulating both physiology and pathology still remain elusive. We recently developed a novel mathematical approach to decompose time-series gene expression data and reveal hidden oscillations separate from the 24h rhythmicity. We unexpectedly discovered that, in addition to the UPR genes, the 12h rhythmicity is much more prevalent than was initially thought and is widely found in metabolic genes in mouse liver. We further uncovered prevalent 12h oscillations in liver metabolism in vivo. The fact that the 12h rhythmicity remains intact in the absence of functional 24h circadian clock suggests that the 12h rhythm is established and maintained by an independent clock component distinct from the 24h circadian clock. The objective of this proposal is to use the liver as a model organ to test the hypothesis that: 1) there is an equally important molecular clock establishing the 12h period rhythmicity, which coordinates oscillations of ER stress and dynamic bioenergetic metabolism to ensure systemic homeostasis, and 2) that the hepatic 12h clock is transcriptionally regulated by SRC-3 and XBP1s. In Aim 1 the transcriptional regulation of the 12h rhythm of gene expression and metabolism will be investigated with a focus on the interplay between UPR TF XBP1 and coactivator SRC-3 using ChIP-Seq, RNA-Seq, metabolomics and mathematical modeling approaches. In Aim 2, whether XBP1s/SRC-3 dependent 12-hour clock dysregulation contributes to chronic ER stress-induced NAFLD will be determined. In Aim 3, whether XBP1s/SRC-3 dependent 12-hour clock dysregulation contributes to nutritional challenge-induced NAFLD will be determined.

项目 3 - 项目摘要除了经过充分研究的昼夜节律之外，还有一组以第二次谐波（12 小时周期）循环的基因在小鼠体内的几个外周组织中发现了昼夜节律。基因表现出明显的 12 小时节律性丰富于内质网 (ER) 应激和未折叠蛋白反应 (UPR) 途径，这是普遍保守的适应性反应，以应对未折叠蛋白质的积累急诊室。尽管有这些初步发现，体内 12 小时节律的确切患病率及其与生物钟，12 小时节律是如何在分子水平上建立的，以及它在调节这两个方面的精确作用生理学和病理学仍然难以捉摸。我们最近开发了一种新颖的数学方法分解时间序列基因表达数据并揭示与 24 小时节律分开的隐藏振荡。我们意外地发现，除了 UPR 基因之外，12 小时节律性比最初被认为并广泛存在于小鼠肝脏的代谢基因中。我们进一步发现流行的 12 小时体内肝脏代谢的振荡。事实上，在缺乏功能性的情况下，12 小时节律保持完整 24 小时昼夜节律时钟表明 12 小时节律是由一个独立的时钟建立和维持的与 24 小时生物钟不同的组成部分。该提案的目标是使用肝脏作为模型检验以下假设的器官： 1) 存在一个同样重要的分子钟，建立 12 小时周期节律性，协调内质网应激和动态生物能量代谢的振荡，以确保全身性体内平衡，2) 肝脏 12 小时时钟由 SRC-3 和 XBP1 转录调节。目标 1 将重点研究基因表达和代谢的 12 小时节律的转录调控使用 ChIP-Seq、RNA-Seq、代谢组学研究 UPR TF XBP1 和共激活剂 SRC-3 之间的相互作用数学建模方法。在目标 2 中，XBP1s/SRC-3 是否依赖 12 小时时钟失调将确定导致慢性 ER 应激诱发的 NAFLD 的因素。在目标 3 中，是否依赖 XBP1s/SRC-3 将确定 12 小时生物钟失调是否会导致营养挑战引起的 NAFLD。