Role of PPARG the PPARG Target Gene RBP7 in the Endothelium
PPARG 的作用 PPARG 靶基因 RBP7 在内皮细胞中的作用
基本信息
- 批准号:9249635
- 负责人:
- 金额:$ 61.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAll-Trans-RetinolAnti-Inflammatory AgentsAnti-inflammatoryAntioxidantsAortaBindingBiological AssayBiologyBlood VesselsCRISPR/Cas technologyCardiovascular DiseasesCardiovascular systemCarotid ArteriesCell NucleusCellsCellular biologyCerebrovascular CirculationComplementDataDevelopmentDominant-Negative MutationEndothelial CellsEndotheliumExhibitsFamilyFunctional disorderGene ExpressionGene Expression ProfilingGene TargetingGenesGeneticGenetic TranscriptionHigh Fat DietHumanHypertensionImpairmentKnock-in MouseKnock-outLaboratoriesLacZ GenesLigand BindingLigandsLipidsMediatingMolecularMonitorMusMutationNitric OxideNuclear TranslocationOxidation-ReductionOxidative StressPPAR alphaPPAR deltaPPAR gammaPPARG genePathway interactionsPhenotypePhysiologyPlayRNA InterferenceRXRReactive Oxygen SpeciesRegulationReportingResearch PersonnelRetinol Binding ProteinsRisk FactorsRoleSignal TransductionStressSuperoxidesTechniquesTestingTranscriptional RegulationTransgenic MiceVasomotoradiponectinbasilar arterycardiovascular risk factorearly onsetefficacy testingendothelial dysfunctionfatty acid-binding proteinsgenome editinginnovationinsulin sensitivitylipid transportmutantnoveloverexpressionpublic health relevanceresponserosiglitazoneselective expressiontranscription factortranscriptome sequencingvasoconstriction
项目摘要
DESCRIPTION (provided by applicant): PPARγ is a ligand activated transcription factor best known for its role in regulating insulin sensitivity and adipose tissue development and expansion. There is now convincing evidence to support an important beneficial role for endothelial PPARγ in the regulation of endothelial function. However, little is known about the transcriptional targets for PPARγ, how PPARγ selectively activates some targets over others, and their mechanisms of action in the endothelium. Selective expression of a dominant negative mutant of PPARγ in the endothelium (E-V290M) has no effect on endothelial function in aorta, carotid or basilar arteries in young transgenic mice at baseline, but induces severe dysfunction if
the mice are challenged by a high fat diet, Ang-II, or are old. The cerebral circulation is particularly sensitive to oxidative stress in response to the interference with PPARγ signaling. Conversely, increased expression of wildtype PPARγ specifically in the endothelium (E- PPARγ-WT) reduced vasoconstriction to Ang-II. These data strongly suggest that PPARγ plays a protective role in the endothelium under stressed conditions, and the dysfunction resulting from PPARγ impairment is caused by oxidative stress. We identified retinol-binding protein 7 (RBP7) as a PPARγ target gene in the endothelium. RBP7 is an intracellular retinol binding protein belonging to the family of intracellular lipid and fatty acid-binding proteins. Expression of RBP7 is endothelial cell-specific. RBP7-deficient mice exhibit the same high fat diet-induced and Ang-II-induced phenotype as E-V290M mice which selectively express a dominant negative mutant of PPARγ in the endothelium. This led us to consider the innovative concept that the beneficial effects of PPARγ in the endothelium may be mediated by RBP7. Intracellular lipid and fatty acid binding proteins have been reported to bind ligands which activate other ligand activated transcription factors. Thus conceptually, we hypothesize that PPARγ and RBP7 may form a transcriptional regulatory loop (or hub) in endothelial cells, which is required to support an anti
oxidant state and when impaired induces a pro-oxidant state. We will examine this concept in two Specific Aims. Specific Aim 1 will test the hypotheses that a) the beneficial effects of wildtype PPARγ over-expression in the endothelium require RBP7, b) that the effects of RBP7 are mediated by its retinol-binding and lipid transport activity, and c) RBP7 is required for the PPARγ- mediated anti-oxidant response, including the expression and function of endothelial adiponectin. Specific Aim 2 will evaluate the molecular mechanisms by which RBP7 regulates PPARγ transcriptional activity by testing the hypothesis that RBP7 with its intrinsic retinol binding and nuclear translocation activity is required for transcriptional activity of PPARγ.
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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Curt Daniel Sigmund其他文献
Curt Daniel Sigmund的其他文献
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{{ truncateString('Curt Daniel Sigmund', 18)}}的其他基金
PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness
PPARG 依赖性机制控制内皮-平滑肌协调、动脉压、血管舒缩功能和动脉僵硬度
- 批准号:
10337230 - 财政年份:2019
- 资助金额:
$ 61.64万 - 项目类别:
PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness
PPARG 依赖性机制控制内皮-平滑肌协调、动脉压、血管舒缩功能和动脉僵硬度
- 批准号:
10092211 - 财政年份:2019
- 资助金额:
$ 61.64万 - 项目类别:
PPARG-dependent Mechanisms Control Endothelial-Smooth Muscle Coordination, Arterial Pressure, Vasomotor Function and Arterial Stiffness
PPARG 依赖性机制控制内皮-平滑肌协调、动脉压、血管舒缩功能和动脉僵硬度
- 批准号:
10565914 - 财政年份:2019
- 资助金额:
$ 61.64万 - 项目类别:
PPG-Genetic and Signaling Mechanisms in the Central Regulation of Blood Pressure
PPG-血压中枢调节的遗传和信号机制
- 批准号:
9278663 - 财政年份:2016
- 资助金额:
$ 61.64万 - 项目类别:
Hypertension: Role of Smooth Muscle Cullin-3 and the CRL3 Complex
高血压:平滑肌 Cullin-3 和 CRL3 复合体的作用
- 批准号:
8956718 - 财政年份:2015
- 资助金额:
$ 61.64万 - 项目类别:
Novel Mechanism Regulating RAS Activity in the Brain: Role in Neurogenic Hypertension
调节大脑 RAS 活性的新机制:在神经源性高血压中的作用
- 批准号:
10213809 - 财政年份:2007
- 资助金额:
$ 61.64万 - 项目类别:
PPG-Genetic and Signaling Mechanisms in the Central Regulation of Blood Pressure
PPG-血压中枢调节的遗传和信号机制
- 批准号:
7433915 - 财政年份:2007
- 资助金额:
$ 61.64万 - 项目类别:
Role of the brain Renin-Angiotensin Sys. in Cardiovas and Metabolic Regulation
大脑肾素-血管紧张素系统的作用。
- 批准号:
8651937 - 财政年份:2007
- 资助金额:
$ 61.64万 - 项目类别:
Genetic and Signaling Mechanisms in the Central Regulation of Blood
血液中枢调节的遗传和信号机制
- 批准号:
9977790 - 财政年份:2007
- 资助金额:
$ 61.64万 - 项目类别:
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