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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：
8898941
负责人：
Adam Raymond Wende
金额：
$ 14.41万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-02 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898941
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

Project Summary 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.

项目总结