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：
9975156
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9975156
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 Liver diseases 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 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-项目摘要除了研究良好的昼夜节律之外，在第二个（12h期）谐波中循环的基因群在体内的几个外周血组织中发现了昼夜节律的节奏性。表现出明显的基因 12H节奏性富含内质网（ER）应激和展开的蛋白质反应（UPR）途径，这些途径是对应对展开的蛋白质积累的普遍保守的适应性反应急诊室。尽管有这些初步发现，但体内12h节奏的确切流行率，它与昼夜节律时钟，如何在分子水平上建立12H节奏及其在调节两者中的精确作用生理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，并揭示隐藏的振荡与24h节奏性分开。我们出乎意料地发现，除了UPR基因外，12H节奏性比最初被认为，在小鼠肝脏的代谢基因中被广泛发现。我们进一步发现了普遍的12h 体内肝脏代谢的振荡。在没有功能的情况下，12H节奏性保持完整的事实 24小时的昼夜节律表明，12h节奏是由独立时钟建立和维护的组件与24小时昼夜节律不同。该建议的目的是将肝脏用作模型器官测试以下假设：1）建立12h时期的分子时钟同样重要节奏性，它可以协调ER应力和动态生物能代谢的振荡，以确保系统性稳态，以及2）肝12h时钟在转录下由SRC-3和XBP1S调节。在目标1中将研究基因表达和代谢的12h节奏的转录法规，重点是在UPR TF XBP1与共激活器SRC-3之间的相互作用上，使用芯片序列，RNA-SEQ，代谢组学和数学建模方法。在AIM 2中，XBP1S/SRC-3是否取决于12小时的时钟失调将确定有助于慢性ER应力引起的NAFLD。在AIM 3中，XBP1/SRC-3是否依赖将确定12小时的时钟失调有助于营养挑战引起的NAFLD。