Metabolic Signals Regulating GLUT4 Expression in Vivo
调节体内 GLUT4 表达的代谢信号
基本信息
- 批准号:8307908
- 负责人:
- 金额:$ 29.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-06-01 至 2014-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAnimal ModelBindingBinding ProteinsBinding SitesBiochemicalBiological AssayClinical ResearchComplexDNA StructureDevelopmentDiabetes MellitusDiabetic mouseDiseaseDockingDown-RegulationElementsEnhancersExerciseFamilyFastingGLUT 4 proteinGLUT4 geneGene ExpressionGenesGenetic TranscriptionGlucose TransporterGoalsHDAC5 geneHistone DeacetylaseHomologous GeneHormonalHumanHypersensitivityIn VitroIndiumInsulinInsulin ResistanceInterventionLaboratoriesLearningLigand Binding DomainLigandsLightLiverMediatingMetabolicMetabolic syndromeMetabolismModelingMolecularMolecular TargetMusMuscleNon-Insulin-Dependent Diabetes MellitusNucleic Acid Regulatory SequencesOvernutritionPhysiologicalProductionProtein IsoformsProteinsRegulationResearchRoleSignal TransductionSiteTestingTherapeutic InterventionTissuesTranscription CoactivatorTranscription Initiation SiteTranscriptional ActivationTranscriptional RegulationTransgenic MiceWorkbaseblood glucose regulationdrug discoveryfeedingglucose uptakein vivoloss of function mutationmouse modelmuscle enhancer factor-2Amyocyte-specific enhancer-binding factor 2promoterprotein complexpublic health relevancereceptortranscription factor
项目摘要
DESCRIPTION (provided by applicant): GLUT4 is the isoform principally responsible for insulin-mediated glucose uptake in mammalian tissues. Glucose homeostasis is sensitive to changes in GLUT4 levels. Modulation of GLUT4 levels is therefore an attractive molecular target for therapeutic intervention in insulin-resistant states, including diabetes mellitus. A straightforward approach to enhance GLUT4 expression is to increase the transcription rate of the gene. GLUT4 gene expression is transcriptionally regulated in physiologic states such as insulin-deficiency and exercise, and it is likely that a pharmacological intervention can be developed to enhance Glut4 gene transcription. To reach this goal, we must first understand the molecular basis for transcriptional regulation of the GLUT4 gene. Using transgenic mice, we have shown that cis-elements regulating the human Glut4 promoter are located within 895 bp immediately 5' of the transcription initiation site. This region contains two major regulatory domains, referred to as Domain I and the MEF2 domain. These elements function cooperatively to support regulated expression of GLUT4. The MEF2 domain binds isoforms of the Myocyte Enhancer Factor 2 (MEF2) family of transcription factors, while Domain I binds GEF (GLUT4 Enhancer Factor), a transcriptional activator identified and cloned in our laboratory. MEF2 isoforms and GEF form a protein complex in vivo; however, the function of this complex in regulating gene transcription is not known. A conserved Liver Receptor X (LXRE) domain is located immediately adjacent to the MEF2 site. The functional role of this element has not been determined. We hypothesize that both the tissue-specific and the hormonal and/or metabolic regulation of the GLUT4 gene are carried out through these regulatory domains and their cognate binding proteins. The primary goal of this proposal is to understand the molecular mechanisms of the tissue-specific and hormonal/metabolic regulation of GLUT4 gene transcription. To achieve these goals, we propose the following specific aims: 1) To determine the functional role of GEF in GLUT4 transcriptional activation; 2) To understand the role of HDAC function in regulation of GLUT4 expression 3) ) To determine the contribution of the GLUT4 LXRE in mediating metabolic signals to the GLUT4 promoter. Completion of these aims will inform us what signals changes in GLUT4 expression in a variety of altered metabolic conditions of insulin- deficiency or insulin resistance. These conditions each result in down-regulation of GLUT4 expression, but it is unclear if this is by a single mechanism. Completion of the aims of this proposal will help us to understand more about the GLUT4 promoter and more about the intracellular signaling during insulin- deficiency and insulin-resistance.
PUBLIC HEALTH RELEVANCE: Diseases characterized by insulin resistance such as diabetes mellitus and metabolic syndrome are increasingly prevalent around the world. Animal models and human clinical studies suggest that increasing the production of the insulin- responsive glucose transporter (GLUT4) protein is a good way to treat these diseases. The research goals of this project are very important for learning how we can increase the production of the GLUT4 protein. This work will facilitate drug discovery to achieve this desired goal.
描述(由申请方提供):GLUT 4是主要负责哺乳动物组织中胰岛素介导的葡萄糖摄取的同种型。葡萄糖稳态对GLUT 4水平的变化敏感。因此,GLUT 4水平的调节是用于胰岛素抵抗状态(包括糖尿病)中的治疗干预的有吸引力的分子靶标。增强GLUT 4表达的直接方法是增加基因的转录速率。GLUT 4基因表达在生理状态如胰岛素缺乏和运动中受到转录调节,并且很可能可以开发药物干预来增强Glut 4基因转录。为了达到这一目标,我们必须首先了解GLUT 4基因转录调控的分子基础。使用转基因小鼠,我们已经表明,顺式元件调节人Glut 4启动子位于895 bp内的转录起始位点的5'。该区域包含两个主要的调节结构域,称为结构域I和MEF 2结构域。这些元件协同作用以支持GLUT 4的调节表达。MEF 2结构域结合肌细胞增强因子2(MEF 2)家族转录因子的亚型,而结构域I结合GEF(GLUT 4增强因子),GEF是我们实验室鉴定和克隆的转录激活因子。MEF 2亚型和GEF在体内形成蛋白复合物;然而,该复合物在调节基因转录中的功能尚不清楚。一个保守的肝受体X(LXRE)结构域位于紧邻MEF 2位点。这一部分的职能尚未确定。我们推测,无论是组织特异性和激素和/或代谢的GLUT 4基因的调节是通过这些调控结构域和它们的同源结合蛋白。该提案的主要目标是了解GLUT 4基因转录的组织特异性和激素/代谢调节的分子机制。为了实现这些目标,我们提出了以下具体目标:1)确定GEF在GLUT 4转录激活中的功能作用; 2)了解HDAC功能在GLUT 4表达调控中的作用; 3)确定GLUT 4 LXRE在介导代谢信号到GLUT 4启动子中的贡献。这些目标的完成将告知我们在胰岛素缺乏或胰岛素抵抗的各种改变的代谢条件下GLUT 4表达的信号变化。这些条件各自导致GLUT 4表达下调,但尚不清楚这是否是由单一机制引起的。本课题的完成将有助于我们进一步了解GLUT 4启动子以及胰岛素缺乏和胰岛素抵抗过程中的细胞内信号转导。
公共卫生相关性:以胰岛素抵抗为特征的疾病如糖尿病和代谢综合征在世界范围内日益流行。动物模型和人类临床研究表明,增加胰岛素反应性葡萄糖转运蛋白(GLUT 4)蛋白的产生是治疗这些疾病的好方法。该项目的研究目标对于了解如何增加GLUT 4蛋白的产量非常重要。这项工作将促进药物发现,以实现这一预期目标。
项目成果
期刊论文数量(0)
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ANN LOUISE OLSON其他文献
ANN LOUISE OLSON的其他文献
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{{ truncateString('ANN LOUISE OLSON', 18)}}的其他基金
Does age-dependent PFKFB3 down-regulation alter adipose tissue function
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- 批准号:
10563615 - 财政年份:2022
- 资助金额:
$ 29.07万 - 项目类别:
Metabolic Signals Regulating GLUT4 Expression in Vivo
调节体内 GLUT4 表达的代谢信号
- 批准号:
8489286 - 财政年份:2010
- 资助金额:
$ 29.07万 - 项目类别:
Metabolic Signals Regulating GLUT4 Expression in Vivo
调节体内 GLUT4 表达的代谢信号
- 批准号:
8052717 - 财政年份:2010
- 资助金额:
$ 29.07万 - 项目类别:
Metabolic Signals Regulating GLUT4 Expression in Vivo
调节体内 GLUT4 表达的代谢信号
- 批准号:
7912781 - 财政年份:2010
- 资助金额:
$ 29.07万 - 项目类别:
Metabolic Signals Regulating GLUT4 Expression in vivo
调节体内 GLUT4 表达的代谢信号
- 批准号:
7813165 - 财政年份:2009
- 资助金额:
$ 29.07万 - 项目类别:
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