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:
- 金额:$ 35.66万
- 依托单位:
- 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:
- 关键词:ARNTL geneAblationAdipose tissueAgingAnimalsArchitectureBehavioralBindingBioenergeticsBiological RhythmBioperiodicityBody TemperatureCellsCellular Metabolic ProcessChIP-seqChemicalsChromatinChronicCircadian RhythmsClinicalColonCuesDataDevelopmentDiseaseEndoplasmic ReticulumEnsureExhibitsFatty LiverGene ClusterGene ExpressionGenesGenetic TranscriptionHeartHepaticHigh Fat DietHomeostasisHormonesHourHumanHypothalamic structureIn VitroJet Lag SyndromeKidneyLifeLightLiverLungMaintenanceMalignant NeoplasmsMediator of activation proteinMedicalMetabolicMetabolic stressMetabolic syndromeMetabolismMitochondriaMolecularMusNon-Insulin-Dependent Diabetes MellitusNuclear ReceptorsNutritionalObesityOrgan ModelOutputPathologyPathway interactionsPeriodicityPeripheralPhysiologicalPhysiologyPlanet EarthPrevalenceProcessProteinsPublishingRNA SplicingResearchRoleRunningSeriesSystemTestingTimeTissuesTranscriptional RegulationWorkXBP1 genebasecircadiancircadian pacemakercognitive performanceendoplasmic reticulum stressepidemiology studyfatty liver diseasegene networkin vivoliver metabolismmathematical methodsmathematical modelmetabolomicsmolecular clockmouse modelnon-alcoholic fatty liver diseasenovelpreventprogramsresponseshift worksleep patterntranscription factortranscriptome 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 -项目概要
除了已经被充分研究的昼夜节律外,一组以二次谐波(12小时周期)循环的基因,
在小鼠体内的几种外周组织中发现了昼夜节律的基因。
12小时节律性在内质网(ER)应激和未折叠蛋白反应(UPR)中富集
途径,这是普遍保守的适应性反应,以科普积累的未折叠蛋白质,
尽管有这些初步的发现,体内12小时节律的确切流行率,其与ER的关系,
生物钟,12小时节律如何在分子水平上建立,以及它在调节生物钟和生物钟中的精确作用。
生理学和病理学仍然是难以捉摸的。我们最近开发了一种新的数学方法,
对时间序列基因表达数据进行分解,揭示隐藏在24小时节律性之外的振荡。
我们意外地发现,除了UPR基因,12小时节律性比其他基因更为普遍。
最初被认为是在小鼠肝脏的代谢基因中广泛发现的。我们进一步发现了流行的12小时
在体内肝脏代谢的振荡。事实上,12小时的节律性保持完整的功能性的情况下,
24小时生物钟提示12小时节律是由一个独立的生物钟建立和维持的
该建议的目的是使用肝脏作为模型,
器官来检验假设:1)有一个同样重要的分子钟建立12小时周期
节律性,协调ER应激和动态生物能量代谢的振荡,以确保系统性
体内平衡,和2)肝脏12小时时钟是由SRC-103和XBP 1转录调节。
重点研究基因表达和代谢12小时节律的转录调节
使用ChIP-Seq、RNA-Seq、代谢组学和
在目标2中,XBP 1 s/SRC-B13依赖的12小时生物钟失调是否
在目的3中,是否XBP 1 s/SRC-BP 3依赖性的细胞因子在慢性内质网应激诱导的NAFLD中起作用将被确定。
12小时生物钟失调有助于营养挑战-将确定糖尿病诱导的NAFLD。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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BERT W O'MALLEY其他文献
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{{ truncateString('BERT W O'MALLEY', 18)}}的其他基金
Core A (Administrative/Bioinformatics/Statistics)
核心A(管理/生物信息学/统计学)
- 批准号:
10153757 - 财政年份:2018
- 资助金额:
$ 35.66万 - 项目类别:
Nuclear receptors and their Coactivators as Mediators of Systems Metabolism
核受体及其共激活剂作为系统代谢的调节剂
- 批准号:
10153756 - 财政年份:2018
- 资助金额:
$ 35.66万 - 项目类别:
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
- 批准号:
10153762 - 财政年份:2018
- 资助金额:
$ 35.66万 - 项目类别:
Nuclear receptors and their Coactivators as Mediators of Systems Metabolism
核受体及其共激活剂作为系统代谢的调节剂
- 批准号:
10421277 - 财政年份:2018
- 资助金额:
$ 35.66万 - 项目类别:
Nuclear receptors and their Coactivators as Mediators of Systems Metabolism
核受体及其共激活剂作为系统代谢的调节剂
- 批准号:
9975144 - 财政年份:2018
- 资助金额:
$ 35.66万 - 项目类别:
Core A (Administrative/Bioinformatics/Statistics)
核心A(管理/生物信息学/统计学)
- 批准号:
10421278 - 财政年份:2018
- 资助金额:
$ 35.66万 - 项目类别:
The ERbeta/SRC-1 isoform complex drives endometriosis progression
ERbeta/SRC-1亚型复合物驱动子宫内膜异位症进展
- 批准号:
8823016 - 财政年份:2014
- 资助金额:
$ 35.66万 - 项目类别:
The ERbeta/SRC-1 isoform complex drives endometriosis progression
ERbeta/SRC-1亚型复合物驱动子宫内膜异位症进展
- 批准号:
9258329 - 财政年份:2014
- 资助金额:
$ 35.66万 - 项目类别:
The ERbeta/SRC-1 isoform complex drives endometriosis progression
ERbeta/SRC-1亚型复合物驱动子宫内膜异位症进展
- 批准号:
8893195 - 财政年份:2014
- 资助金额:
$ 35.66万 - 项目类别:
The ERbeta/SRC-1 isoform complex drives endometriosis progression
ERbeta/SRC-1亚型复合物驱动子宫内膜异位症进展
- 批准号:
8837524 - 财政年份:2014
- 资助金额:
$ 35.66万 - 项目类别:
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