Project 2: Coordinate regulation of liver energy balance by PPARalpha/SRC-1 and FXR/SRC-2
Project 2: Coordinate regulation of liver energy balance by PPARalpha/SRC-1 and FXR/SRC-2
批准号:
10153761
负责人:
DAVID D MOORE
金额:
$35.66万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2023-04-30
关键词:
Adipose tissueAgonistAlbuminsAutophagocytosisBile AcidsBindingBlood Coagulation FactorBrainCarbohydratesComplementComplexDrug usageEnterohepatic CirculationFamilyFastingFatty AcidsFibratesGenesGenetic TranscriptionGluconeogenesisGoalsHepaticHepatocyteHomebound PersonsHomeostasisHumanIn VitroIndividualKnockout MiceLigandsLipidsLiverMass Spectrum AnalysisMediatingMediator of activation proteinMetabolicMetabolic PathwayMetabolic syndromeMetabolismMonkeysMusNuclear ReceptorsNutrientOutputPPAR alphaPathway interactionsPharmaceutical PreparationsProductionProteinsProteomicsRXRRegulationRepressionResponse ElementsRoleSerumSiteStructureSystemTestingTherapeutic EffectTranscription CoactivatorTranscription Repressorabsorptionbasecholestatic liver diseaseenergy balancefatty acid oxidationfeedinggenome-wideglucose uptakein vivoinsightlipid biosynthesisliver functionmembermetabolomicsnuclear receptor coactivator 1programsreceptorrecruitresponsetranscriptomics
中文摘要
项目2--项目摘要:
--
本项目的主要目标是阐明核受体PPARα和PPAR FXR的主要作用。
联合监管机构包括SRC-1和SRC-2,参与了对肝脏能量和平衡的全面控制。PPARα在未来几年被激活。
禁食状态,促进脂肪酸氧化和糖异生。在美联储的状态下,FXR基因被激活,并被抑制。
糖异生。PPARα家族和FXR家族的转录调控功能是由PPAR辅活化子家族成员介导的。
而且,这个项目管理团队的成员已经被证明,SRC-1和SRC-2也是中央监管机构。
肝脏的能量和平衡。SRC-2促进肝脏的状态和功能,包括血糖和血脂的摄取。
在禁食的情况下,吸收、释放和释放SRC-2的活性受到抑制。相比之下,SRC-1的吸收、吸收和SRC-1的活性是由禁食和空腹引起的。
在这个禁食的状态下,糖异生的激活过程是必不可少的。我们最近被证明,PPARα和FXR。
通过相互拮抗的方式,协调调节肝脏中另一种基本的营养反应,即自噬。
诱导和抑制的影响。在我们的初步研究结果中,我们可以确定肝细胞分泌组是另一个,相当的。
意想不到的潜在目标是补充控制肝脏能量平衡的目标。分泌平衡是一个非常重要的能量来源。
我们可以有更多的证据表明,在PPARα的作用下,FXR激活了肝脏的内分泌组。
压制它。根据这些结果,我们的总体预测假说是,PPARα与SRC-1,和FXR在演唱会上合作。
与SRC-2合作,将在未来的肝脏中规范能源利用和生产的广泛途径,以更好地维持能源。
平衡。我们将提出第三点,旨在对这一假说进行批判性的检验,并探索产生这些影响的主要机制基础。
1.完成人类主要角色的全基因组、全基因组、全转录、全蛋白质组和全代谢全基因组。
PPARα和FXR在美联储和美联储的会议上禁食了肝脏。他们定义了他们在反对的会议中的主要角色。
PPARα和FXR在体内的作用。3.确定了实现PPAR/RXR相互转化的结构和功能基础。
异源二聚体来自配体依赖和转录激活因子,依赖于IR-1位点,依赖于配体依赖转录激活因子。
抑制子位于dr-1基因位点上,它们和共同定义了与这两种基因相关的监管机构。
英文摘要
Project 2 - Project Summary
The primary goal of this project is to elucidate the roles of the nuclear receptors PPARα and FXR, and the
coregulators SRC-1 and SRC-2, in the overall control of energy balance in the liver. PPARα is activated in the
fasted state, promoting fatty acid oxidation and gluconeogenesis. FXR is activated in the fed state and represses
gluconeogenesis. Transcriptional functions of PPARα and FXR are mediated by the SRC family of coactivators,
and the members of this Program Project team have shown that SRC-1 and SRC-2 are also central regulators
of liver energy balance. SRC-2 promotes hepatic fed state functions, including glucose uptake and lipid
absorption, and SRC-2 activity is inhibited in the fasted state. In contrast, SRC-1 is induced by fasting and is
essential for activation of gluconeogenesis in the fasted state. We have recently shown that PPARα and FXR
coordinately regulate another fundamental nutrient response in the liver, autophagy, via mutually antagonistic
effects of induction and repression. Our preliminary results identify the hepatic secretome as another, quite
unexpected potential target for complementary control of liver energy balance. Secretion is a very energy
intensive function of the liver, and we have evidence that FXR activates the hepatic secretome, while PPARα
represses it. Based on these results, our overall hypothesis is that PPARα, in concert with SRC-1, and FXR, in
concert with SRC-2, regulate broad pathways of energy utilization and production in the liver to maintain energy
balance. We propose 3 aims to critically test this hypothesis and explore the mechanistic basis for these effects.
1. Complete the genome wide cistromic, transcriptomic, proteomic and metabolomic profiling of the roles of
PPARα and FXR in the fed and fasted liver. 2. Define the role of SRC-1, SRC-2 and NCoR in the opposing
effects of PPARα and FXR in vivo. 3. Define the structural and functional basis for the conversion of FXR/RXR
heterodimers from ligand dependent transcriptional activators on IR-1 sites to ligand dependent transcriptional
repressors on DR-1 sites, and define the coregulators associated with both.
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Project 2: Coordinate regulation of liver energy balance by PPARalpha/SRC-1 and FXR/SRC-2
-
批准号:10421283
-
项目类别:
-
资助金额:$35.66万
-
财政年份:2018
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负责人:DAVID D MOORE
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依托单位:
Function of the Nuclear Receptor LRH-1
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批准号:7632978
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项目类别:
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资助金额:$38.38万
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财政年份:2009
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负责人:DAVID D MOORE
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依托单位:
Function of the Nuclear Receptor LRH-1
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批准号:7895885
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项目类别:
-
资助金额:$38.38万
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财政年份:2009
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负责人:DAVID D MOORE
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依托单位:
Nuclear Receptor Function in Hepatic Pathology
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批准号:7350611
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项目类别:
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资助金额:$33.12万
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财政年份:2007
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负责人:DAVID D MOORE
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依托单位:
Functions of the Nuclear Receptor SHP
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批准号:7210533
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项目类别:
-
资助金额:$44.13万
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财政年份:2005
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负责人:DAVID D MOORE
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依托单位:
Functions of the Nuclear Receptor SHP
-
批准号:7030908
-
项目类别:
-
资助金额:$44.12万
-
财政年份:2005
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负责人:DAVID D MOORE
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依托单位:
Functions of the Nuclear Receptor SHP
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批准号:6925670
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项目类别:
-
资助金额:$43.87万
-
财政年份:2005
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负责人:DAVID D MOORE
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依托单位:
Functions of the Nuclear Receptor SHP
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批准号:7408571
-
项目类别:
-
资助金额:$44.54万
-
财政年份:2005
-
负责人:DAVID D MOORE
-
依托单位:
Metabolic Regulation by the Nuclear Receptor CAR
-
批准号:7003683
-
项目类别:
-
资助金额:$31.6万
-
财政年份:2003
-
负责人:DAVID D MOORE
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依托单位:
Metabolic Regulation by the Nuclear Receptor CAR
-
批准号:6567797
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项目类别:
-
资助金额:$32.36万
-
财政年份:2003
-
负责人:DAVID D MOORE
-
依托单位:
Metabolic Regulation by the Nuclear Receptor CAR
-
批准号:6833952
-
项目类别:
-
资助金额:$32.36万
-
财政年份:2003
-
负责人:DAVID D MOORE
-
依托单位:
Metabolic Regulation by the Nuclear Receptor CAR
-
批准号:6721370
-
项目类别:
-
资助金额:$32.36万
-
财政年份:2003
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负责人:DAVID D MOORE
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依托单位:
Function of SHP
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批准号:6589548
-
项目类别:
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资助金额:$17.72万
-
财政年份:2002
-
负责人:DAVID D MOORE
-
依托单位:
SRC-2 Mediates the Preventative Effects of LRH-1 for NASH in Metabolic Disease
-
批准号:8545165
-
项目类别:
-
资助金额:$34.29万
-
财政年份:2001
-
负责人:DAVID D MOORE
-
依托单位:
Function of SHP
-
批准号:6452764
-
项目类别:
-
资助金额:$17.72万
-
财政年份:2001
-
负责人:DAVID D MOORE
-
依托单位:
SRC-2 Mediates the Preventative Effects of LRH-1 for NASH in Metabolic Disease
-
批准号:8856211
-
项目类别:
-
资助金额:$35.35万
-
财政年份:2001
-
负责人:DAVID D MOORE
-
依托单位:
SRC-2 Mediates the Preventative Effects of LRH-1 for NASH in Metabolic Disease
-
批准号:8419648
-
项目类别:
-
资助金额:$35.35万
-
财政年份:2001
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负责人:DAVID D MOORE
-
依托单位:
ORPHAN RECEPTORS IN ORGANOGENESIS
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批准号:6915468
-
项目类别:
-
资助金额:$8.28万
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财政年份:2000
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负责人:DAVID D MOORE
-
依托单位:
Function of SHP
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批准号:6324284
-
项目类别:
-
资助金额:$17.72万
-
财政年份:2000
-
负责人:DAVID D MOORE
-
依托单位:
ORPHAN RECEPTORS IN ORGANOGENESIS
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批准号:6090344
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项目类别:
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资助金额:$106.34万
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财政年份:2000
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负责人:DAVID D MOORE
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依托单位:
国内基金
海外基金
Agonist-GPR119-Gs复合物的结构生物学研究
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批准号:32000851
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项目类别:青年科学基金项目
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资助金额:24.0万元
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批准年份:2020
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负责人:乔安娜
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依托单位: