Regulation of Circadian Metabolism by the Hepatic Transcription Factor CREBH
肝转录因子 CREBH 对昼夜代谢的调节
基本信息
- 批准号:9913501
- 负责人:
- 金额:$ 30.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-01 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:ARNTL geneAddressAnimal GeneticsAnimal ModelCardiovascular DiseasesCircadian DysregulationCircadian RhythmsCuesCyclic AMP-Responsive DNA-Binding ProteinDevelopmentDietDiurnal RhythmEndoplasmic ReticulumEnergy MetabolismExhibitsFatty LiverFatty acid glycerol estersFundingGenesGenetic TranscriptionGlucoseGoalsHepaticHepatocyteHigh Fat DietHomeostasisHumanHyperlipidemiaImpairmentInflammatoryLXRalpha proteinLife StyleLightLinkLipidsLiverMediatingMetabolicMetabolic DiseasesMetabolic PathwayMetabolic hormoneMetabolic stressMetabolic syndromeMetabolismModelingModernizationMolecularMusNamesNon-Insulin-Dependent Diabetes MellitusNuclear ReceptorsOrganOutputPPAR alphaPathologicPathway interactionsPatientsPeriodicityPhysiologicalPlayPost-Translational Protein ProcessingPreventionProto-Oncogene Proteins c-aktPublic HealthResearchRoleSignal PathwaySignal TransductionSignal Transduction PathwayStressTestingTime-restricted feedingTrans-Activatorsbaseblood glucose regulationcircadiancircadian pacemakercircadian regulationfeedinghuman diseaseinsightliver metabolismmetabolic abnormality assessmentnon-alcoholic fatty liver diseasenovelpreservationresponseshift worksynergismtranscription factor
项目摘要
PROJECT SUMMARY
Dysregulated circadian rhythm is closely associated with human metabolic disease, such as type-2 diabetes,
cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the modern life style, the problem
of irregular circadian rhythm has enormous impact in public health. Although considerable progress has been
made in understanding the connection between circadian rhythm and metabolism, the mechanisms by which
circadian regulators modulate metabolic rhythmicity and its impact in the progression of metabolic disorders
remain to be further elucidated. During the last funding cycle, we defined an endoplasmic reticulum (ER)-resident,
liver-specific transcription factor named CREBH (cyclic-AMP-response element-binding protein H) that can be
activated by a variety of inflammatory and metabolic signals to function as a key regulator of hepatic energy
metabolism. Recently, we have accumulated strong preliminary evidence that CREBH functions as an organ-
specific, diurnal regulator that is critical for preserving the rhythmicity of energy homeostasis. During the circadian
cycle, CREBH activation in the liver is regulated by the core clock oscillator BMAL1, and activated CREBH
interacts with the key circadian metabolic regulators to regulate diurnal rhythm of lipid and glucose homeostasis.
CREBH-deficient mice display impaired rhythmic profiles of lipids and glucose and altered metabolic responses,
and are susceptible to the development of hepatic steatosis and hyperlipidemia. These observations led to our
central hypothesis that CREBH functions as a key transcriptional regulator in the liver that integrates circadian
regulation to hepatic energy homeostasis. Disruption of CREBH-regulated hepatic energy rhythmicity contributes
to or amplifies NAFLD and hyperlipidemia under the metabolic diet or shift working/feeding conditions. To test
this hypothesis, we will utilize molecular and cellular approaches, animal genetics, and circadian metabolic
studies to address the molecular mechanism and pathophysiological significance for CREBH-regulated
metabolic rhythmicity in the progression of NAFLD and hyperlipidemia. We will pursue two complementary
specific aims: Aim 1, to determine the circadian regulation of CREBH and its role in preserving circadian
rhythmicity of energy homeostasis in both physiological and pathological settings; Aim 2, to decipher the
molecular mechanisms by which CREBH integrates circadian regulation to hepatic energy metabolism. Within
the funding period, we anticipate providing significant insights into the molecular mechanism underlying the
integration of circadian regulation to energy metabolism, in which CREBH plays a key role, and determining the
pathophysiological impact of the defined molecular network in metabolic syndrome. Our proposed research will
significantly extend our understanding of the functional relationship between stress-inducible trans-activators
and nuclear receptors and their interaction and synergism in regulating circadian metabolism. The findings from
our proposed research will have important implications in the prevention and treatment of metabolic disease.
项目摘要
昼夜节律失调与人类代谢疾病密切相关,如2型糖尿病,
心血管疾病和非酒精性脂肪肝(NAFLD)。由于现代生活方式,
不规则的昼夜节律对公共卫生有巨大的影响。虽然取得了很大进展,
在理解昼夜节律和新陈代谢之间的联系时,
昼夜节律调节剂调节代谢节律及其在代谢紊乱进展中的作用
仍有待进一步阐明。在上一个资助周期,我们定义了内质网(ER)居民,
一种名为CREBH(环AMP反应元件结合蛋白H)的肝特异性转录因子,
由多种炎症和代谢信号激活,作为肝脏能量的关键调节器发挥作用
新陈代谢.最近,我们已经积累了强有力的初步证据,CREBH功能作为一个器官-
特定的昼夜调节剂,对于保持能量稳态的节律性至关重要。在昼夜节律中,
在一个循环中,肝脏中的CREBH激活由核心时钟振荡器BMAL 1调节,并且激活的CREBH
与关键的昼夜代谢调节剂相互作用,以调节脂质和葡萄糖稳态的昼夜节律。
CREBH缺陷小鼠表现出脂质和葡萄糖节律性受损以及代谢反应改变,
并且易发生肝脂肪变性和高脂血症。这些观察导致我们
核心假设CREBH作为肝脏中整合昼夜节律的关键转录调节因子发挥作用
调节肝脏能量平衡。CREBH调节的肝脏能量节律性的破坏有助于
在代谢性饮食或轮班工作/喂养条件下,可能导致或放大NAFLD和高脂血症。测试
这个假设,我们将利用分子和细胞的方法,动物遗传学,昼夜代谢,
研究以解决CREBH调节的分子机制和病理生理学意义,
代谢节律性在NAFLD和高脂血症的进展。我们将寻求两个互补的
具体目的:目的1,确定CREBH的昼夜节律调节及其在维持昼夜节律中的作用。
在生理和病理环境中能量稳态的节律性;目的2,
CREBH将昼夜节律调节整合到肝脏能量代谢的分子机制。内
在资助期内,我们预计将提供重要的见解的分子机制,
整合昼夜节律调节能量代谢,其中CREBH发挥关键作用,并决定
代谢综合征分子网络的病理生理学影响我们的研究计划将
显著扩展了我们对应激诱导反式激活因子之间功能关系的理解,
以及它们在调节昼夜代谢中的相互作用和协同作用。的结果
我们的研究对预防和治疗代谢性疾病具有重要意义。
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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Kezhong Zhang其他文献
Kezhong Zhang的其他文献
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{{ truncateString('Kezhong Zhang', 18)}}的其他基金
Mitochondrial NAD kinase: function and mechanism in metabolism
线粒体 NAD 激酶:代谢中的功能和机制
- 批准号:
10595014 - 财政年份:2022
- 资助金额:
$ 30.25万 - 项目类别:
Mitochondrial NAD kinase: function and mechanism in metabolism
线粒体 NAD 激酶:代谢中的功能和机制
- 批准号:
10418364 - 财政年份:2022
- 资助金额:
$ 30.25万 - 项目类别:
Regulation of Hepatic Steatosis by an ER Stress-Inducible Transcription Factor CR
内质网应激诱导转录因子 CR 对肝脂肪变性的调节
- 批准号:
8023261 - 财政年份:2011
- 资助金额:
$ 30.25万 - 项目类别:
Hepatic Steatosis and ER Stress-Inducible Transcription Factor CREBH
肝脂肪变性与内质网应激诱导转录因子 CREBH
- 批准号:
8209093 - 财政年份:2011
- 资助金额:
$ 30.25万 - 项目类别:
Hepatic Steatosis and ER Stress-Inducible Transcription Factor CREBH
肝脂肪变性与内质网应激诱导转录因子 CREBH
- 批准号:
8788785 - 财政年份:2011
- 资助金额:
$ 30.25万 - 项目类别:
A novel CREBH-derived hepatokine regulates triglyceride metabolism
一种新型 CREBH 衍生肝因子调节甘油三酯代谢
- 批准号:
10660331 - 财政年份:2011
- 资助金额:
$ 30.25万 - 项目类别:
Hepatic Steatosis and ER Stress-Inducible Transcription Factor CREBH
肝脂肪变性与内质网应激诱导转录因子 CREBH
- 批准号:
8600675 - 财政年份:2011
- 资助金额:
$ 30.25万 - 项目类别:
Hepatic Steatosis and ER Stress-Inducible Transcription Factor CREBH
肝脂肪变性与内质网应激诱导转录因子 CREBH
- 批准号:
8401181 - 财政年份:2011
- 资助金额:
$ 30.25万 - 项目类别:
Airborne Particulate Matter, Endoplasmic Reticulum Stress and Hepatic Lipid Dysre
空气颗粒物、内质网应激和肝脂质异常
- 批准号:
8109851 - 财政年份:2010
- 资助金额:
$ 30.25万 - 项目类别:
Airborne Particulate Matter, Endoplasmic Reticulum Stress and Hepatic Lipid Dysre
空气颗粒物、内质网应激和肝脂质异常
- 批准号:
7991190 - 财政年份:2010
- 资助金额:
$ 30.25万 - 项目类别:
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