Mechanisms of glucose mediated cardiac mitochondrial dysfunction
葡萄糖介导的心脏线粒体功能障碍的机制
基本信息
- 批准号:8225033
- 负责人:
- 金额:$ 13.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-06-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATP Synthesis PathwayAttentionCardiacCardiac MyocytesCardiovascular systemCause of DeathComplications of Diabetes MellitusDNA MethylationDNA Modification ProcessDataDevelopmentDiabetes MellitusEnzymesEpigenetic ProcessExposure toFunctional disorderFutureGene ExpressionGenesGlucoseGlucose TransporterGoalsHeartHeart failureHyperglycemiaHyperlipidemiaIndividualInsulinKnowledgeLeadLinkMass Spectrum AnalysisMediatingMemoryMetabolicMicroarray AnalysisMitochondriaMitochondrial ProteinsModelingModificationMolecularNuclearOxidative PhosphorylationPathogenesisPathway interactionsPhasePlayPositioning AttributePost-Translational Protein ProcessingProcessProteinsProteomeProteomicsReagentRegulationResearchRiskRoleSecondary toSerumStreptozocinTestingTrainingTranscriptional RegulationTransgenesTransgenic Micebasedefined contributiondiabeticdiabetic cardiomyopathyglucose uptakeglycemic controlhistone modificationin vivo Modelinsightinterestmitochondrial dysfunctionmouse modelnovelnovel therapeutic interventionoverexpressionoxidationpublic health relevanceskillstranscription factortransgene expression
项目摘要
DESCRIPTION (provided by applicant): Heart failure is a major cause of death in individuals with diabetes. Heart failure is characterized in part by mitochondrial dysfunction defined by decreased oxidative capacity and ATP synthesis. Diabetes is accompanied by a number of systemic changes including hyperlipidemia and hyperglycemia. A critical barrier in determining the molecular mechanisms that lead to the development of diabetes-related complications has been the availability of appropriate in vivo models to test each independently. To define the role of glucose delivery to the heart in the regulation of mitochondrial function we have developed a mouse model for inducible cardiomyocyte-specific expression of the glucose transporter, GLUT4. Thus allowing us to directly test the role that cardiomyocyte glucose delivery plays in the healthy and diseased heart. Our preliminary data define a model whereby increased glucose delivery in the basal state enhances glucose utilization. In stark contrast, increased glucose delivery in the presence of hyperglycemia accelerates the development of mitochondrial dysfunction. The long-term goal of my research is to determine the mechanisms controlling mitochondrial metabolic function in the heart. In this proposal, we will start by investigating the
role of glucose-mediated mitochondrial regulation by examining glucose-delivery regulated post-translational modification of mitochondrial proteins (Aim 1) and epigenetic control of oxidative phosphorylation (OXPHOS) gene expression (Aim 2). The latter process has recently received significant attention for its contribution to "glycemic memory", defined as the impact that antecedent glucose concentrations have on persistently increasing the risk of diabetic complications independently of current levels of glycemic control. For Specific Aim 1, we will determine the mitochondrial proteins that are modified by the post-translational modification O-linked GlcNAcylation, which is increased with diabetes, and begin to explore the functional consequences of glucose delivery on mitochondrial oxidative capacity and enzymatic function. Studies outlined in Aim 2, will define the role of epigenetic modifications associated with changes in OXPHOS gene expression that are uniquely regulated by glucose. The initial K99 phase of this proposal will facilitate training in aspects of proteomics (2D-PAGE and mass spectroscopy) and epigenetics (histone modifications and DNA methylation). This additional training will provide me with the knowledge and skill set to independently carry out my immediate short-term goal of finding a tenure-track position (R00 phase), necessary to complete the proposal's aims and pursue my interests in defining molecular mechanisms of cardiac dysfunction. Collectively, the completion of these studies will provide fundamental insights into the mechanistic basis for glucose in the development of diabetic cardiomyopathy and mitochondrial dysfunction.
描述(由申请人提供):心力衰竭是糖尿病患者死亡的主要原因。心力衰竭的部分特征在于线粒体功能障碍,其定义为氧化能力和ATP合成降低。糖尿病伴随着许多全身性变化,包括高脂血症和高血糖症。确定导致糖尿病相关并发症发生的分子机制的一个关键障碍是可获得适当的体内模型来独立地测试每种模型。为了确定葡萄糖输送到心脏在线粒体功能调节中的作用,我们开发了一种小鼠模型,用于诱导葡萄糖转运蛋白GLUT 4的心肌细胞特异性表达。从而使我们能够直接测试心肌细胞葡萄糖输送在健康和患病心脏中的作用。我们的初步数据定义了一个模型,即在基础状态下增加葡萄糖输送增强葡萄糖利用。与此形成鲜明对比的是,在高血糖症的存在下增加的葡萄糖递送加速了线粒体功能障碍的发展。我研究的长期目标是确定控制心脏线粒体代谢功能的机制。在本建议书中,我们将首先调查
通过检查葡萄糖递送调节的线粒体蛋白的翻译后修饰(Aim 1)和氧化磷酸化(OXPHOS)基因表达的表观遗传控制(Aim 2),研究葡萄糖介导的线粒体调节的作用。后一过程最近因其对“血糖记忆”的贡献而受到显著关注,所述“血糖记忆”被定义为先前葡萄糖浓度对持续增加糖尿病并发症风险的影响,而与当前血糖控制水平无关。对于特定目标1,我们将确定通过翻译后修饰O-连接GlcNAc化修饰的线粒体蛋白,其随着糖尿病而增加,并开始探索葡萄糖递送对线粒体氧化能力和酶功能的功能后果。目标2中概述的研究将定义与OXPHOS基因表达变化相关的表观遗传修饰的作用,这些表观遗传修饰仅受葡萄糖调节。该提案的初始K99阶段将促进蛋白质组学(2D-PAGE和质谱)和表观遗传学(组蛋白修饰和DNA甲基化)方面的培训。这项额外的培训将为我提供知识和技能,以独立完成我的短期目标,即找到一个终身职位(R 00阶段),这是完成提案目标和追求我对定义心功能障碍分子机制的兴趣所必需的。总的来说,这些研究的完成将为葡萄糖在糖尿病心肌病和线粒体功能障碍发展中的机制基础提供基本的见解。
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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Adam Raymond Wende其他文献
Adam Raymond Wende的其他文献
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{{ truncateString('Adam Raymond Wende', 18)}}的其他基金
Novel roles of PDK2 in heart failure: Regulation of mitochondrial nuclear crosstalk via metabolic regulation and histone acetylation
PDK2 在心力衰竭中的新作用:通过代谢调节和组蛋白乙酰化调节线粒体核串扰
- 批准号:
10635599 - 财政年份:2023
- 资助金额:
$ 13.72万 - 项目类别:
Glucose-Mediated Remodeling of Cardiac DNA Methylation
葡萄糖介导的心脏 DNA 甲基化重塑
- 批准号:
9767852 - 财政年份:2017
- 资助金额:
$ 13.72万 - 项目类别:
Mechanisms of glucose mediated cardiac mitochondrial dysfunction
葡萄糖介导的心脏线粒体功能障碍的机制
- 批准号:
8672908 - 财政年份:2013
- 资助金额:
$ 13.72万 - 项目类别:
Mechanisms of glucose mediated cardiac mitochondrial dysfunction
葡萄糖介导的心脏线粒体功能障碍的机制
- 批准号:
8712542 - 财政年份:2013
- 资助金额:
$ 13.72万 - 项目类别:
Mechanisms of glucose mediated cardiac mitochondrial dysfunction
葡萄糖介导的心脏线粒体功能障碍的机制
- 批准号:
8898941 - 财政年份:2013
- 资助金额:
$ 13.72万 - 项目类别:
Mechanisms of glucose mediated cardiac mitochondrial dysfunction
葡萄糖介导的心脏线粒体功能障碍的机制
- 批准号:
8889296 - 财政年份:2013
- 资助金额:
$ 13.72万 - 项目类别:
Mechanisms of glucose mediated cardiac mitochondrial dysfunction
葡萄糖介导的心脏线粒体功能障碍的机制
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- 资助金额:
$ 13.72万 - 项目类别:
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