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: 8225033
• 负责人: Adam Raymond Wende
• 金额: $ 13.72万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8225033
• 关键词: ATP Synthesis Pathway; Attention; Cardiac; Cardiac Myocytes; Cardiovascular system; Cause of Death; Complications of Diabetes Mellitus; DNA Methylation; DNA Modification Process; Data; Development; Diabetes Mellitus; Enzymes; Epigenetic Process; Exposure to; Functional disorder; Future; Gene Expression; Genes; Glucose; Glucose Transporter; Goals; Heart; Heart failure; Hyperglycemia; Hyperlipidemia; Individual; Insulin; Knowledge; Lead; Link; Mass Spectrum Analysis; Mediating; Memory; Metabolic; Microarray Analysis; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Molecular; Nuclear; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Phase; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Proteome; Proteomics; Reagent; Regulation; Research; Risk; Role; Secondary to; Serum; Streptozocin; Testing; Training; Transcriptional Regulation; Transgenes; Transgenic Mice; base; defined contribution; diabetic; diabetic cardiomyopathy; glucose uptake; glycemic control; histone modification; in vivo Model; insight; interest; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; overexpression; oxidation; public health relevance; skills; transcription factor; transgene expression

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的主要死亡原因。心力衰竭的特征是线粒体功能障碍由氧化能力降低和ATP合成所定义。糖尿病伴随着许多系统性变化，包括高脂血症和高血糖。确定导致与糖尿病相关并发症发展的分子机制的关键障碍是在体内模型中的可用性，可以独立测试每个模型。为了定义葡萄糖递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，用于葡萄糖转运蛋白的诱导性心肌细胞特异性表达Glut4。因此，使我们能够直接测试心肌细胞葡萄糖在健康和患病的心脏中发挥的作用。我们的初步数据定义了一个模型，在基础状态下增加葡萄糖的递送可增强葡萄糖利用率。与形成鲜明对比的是，在高血糖存在下葡萄糖递送增加会加速线粒体功能障碍的发展。我的研究的长期目标是确定控制心脏线粒体代谢功能的机制。在此提案中，我们将首先调查 葡萄糖介导的线粒体调节通过检查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）的作用（AIM 2）。后一个过程最近因其对“血糖记忆”的贡献而受到了极大的关注，该过程被定义为先前的葡萄糖浓度对持续增加糖尿病并发症的风险而与当前血糖控制水平无关的影响。对于特定目标1，我们将确定通过翻译后修饰的O-Linch Glcnacylation修饰的线粒体蛋白，该蛋白质随糖尿病而增加，并开始探索葡萄糖递送对线粒体氧化能力和酶促功能的功能后果。 AIM 2中概述的研究将定义与由葡萄糖唯一调节的Oxphos基因表达变化相关的表观遗传修饰的作用。该提案的最初K99阶段将促进蛋白质组学方面（2d-Page和质谱）和表观遗传学（组蛋白修饰和DNA甲基化）的训练。这项额外的培训将为我提供知识和技能，以独立执行我找到终身轨道位置（R00阶段）的直接短期目标，这是完成该提案的目标所必需的，并追求我对定义心脏功能障碍分子机制的兴趣。总的来说，这些研究的完成将为糖尿病心肌病和线粒体功能障碍的发展提供基本见解。