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：
8473273
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
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：
https://reporter.nih.gov/project-details/8473273
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

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是线粒体功能障碍，即氧化能力和 ATP 合成下降。糖尿病伴随着许多全身变化，包括高脂血症和高血糖。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是否有适当的体内模型来独立测试每种机制。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，用于诱导心肌细胞特异性表达葡萄糖转运蛋白 GLUT4。因此，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所起的作用。我们的初步数据定义了一个模型，通过增加基础状态下的葡萄糖输送可以提高葡萄糖利用率。与此形成鲜明对比的是，高血糖情况下葡萄糖输送的增加会加速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。在本提案中，我们将从调查通过检查葡萄糖输送调节的线粒体蛋白翻译后修饰（目标 1）和氧化磷酸化 (OXPHOS) 基因表达的表观遗传控制（目标 2）来研究葡萄糖介导的线粒体调节的作用。后一个过程最近因其对“血糖记忆”的贡献而受到极大关注，“血糖记忆”的定义是先前的血糖浓度对持续增加糖尿病并发症风险的影响，与当前的血糖控制水平无关。对于具体目标 1，我们将确定通过翻译后修饰 O-连接 GlcNAcNA 酰化修饰的线粒体蛋白（这种修饰随糖尿病而增加），并开始探索葡萄糖输送对线粒体氧化能力和酶功能的功能影响。目标 2 中概述的研究将定义与仅受葡萄糖调节的 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独立实现我的近期短期目标的知识和技能，即寻找终身职位（R00 阶段），这对于完成提案的目标和追求我对定义心脏的分子机制的兴趣是必要的。功能障碍。总的来说，这些研究的完成将为了解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础见解。