Mechanisms of Diabetic Cardiomyopathy: Mitochondria Subpopulations Brought to Foc

糖尿病心肌病的机制：线粒体亚群聚焦

• 批准号: 8139439
• 负责人: John M Hollander
• 金额: $ 0.22万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139439
• 关键词: Affect; Cardiac; Cardiac Myocytes; Cell membrane; Coronary Arteriosclerosis; Diabetes Mellitus; Functional disorder; Generations; Goals; Heart failure; Hyperglycemia; Impairment; Insulin-Dependent Diabetes Mellitus; Mitochondria; Myocardial Infarction; Myocardium; Pathogenesis; Reactive Oxygen Species; Risk; Site; Therapeutic; Therapeutic Intervention; United States; abstracting; design; diabetic; diabetic cardiomyopathy; flexibility; public health relevance; therapeutic development; therapeutic target; tool; Affect; Cardiac; Cardiac Myocytes; Cell membrane; Coronary Arteriosclerosis; Diabetes Mellitus; Functional disorder; Generations; Goals; Heart failure; Hyperglycemia; Impairment; Insulin-Dependent Diabetes Mellitus; Mitochondria; Myocardial Infarction; Myocardium; Pathogenesis; Reactive Oxygen Species; Risk; Site; Therapeutic; Therapeutic Intervention; United States; abstracting; design; diabetic; diabetic cardiomyopathy; flexibility; public health relevance; therapeutic development; therapeutic target; tool

Project Summary / Abstract One to two million people in the United States, suffer from type 1 diabetes mellitus. Diabetic cardiomyopathy is an impairment of heart muscle that exists independently of coronary artery disease, and is associated with diabetes mellitus. Diabetic cardiomyopathy is characterized by contractile dysfunction which contributes to myocardial infarction and heart failure. Hyperglycemia associated with diabetes mellitus, increases reactive oxygen species (ROS) generation. Because the mitochondrion is the primary site for ROS generation, determination of how mitochondria are affected by diabetes mellitus is crucial for understanding the pathogenesis. Examination of mitochondria is complicated by the fact that two mitochondrial subpopulations are present in the cardiomyocyte, interfibrillar mitochondria (IFM), which situate between the contractile apparatus and subsarcolemmal mitochondria (SSM) that exist beneath the plasma membrane. Currently, it is unclear how spatially distinct mitochondrial subpopulations are effected by diabetes mellitus making it difficult to ascertain their specific contribution to diabetic cardiomyopathy. Our long-term goal is to elucidate the mechanisms involved in the pathogenesis of diabetic cardiomyopathy as a prerequisite to the development of therapeutics designed to lessen cardiac complications associated with diabetes mellitus. The central hypothesis of this application is that cardiac IFM are at greater risk from diabetic insult than SSM. The objectives of this application are to determine the effect of diabetic insult on spatially distinct mitochondrial subpopulations, identify key factors that contribute to dysfunction in specific mitochondrial subpopulations, and to develop therapeutics that target spatially distinct mitochondria subsets. Public Health Relevance Statement The proposed studies will enhance our understanding of the pathogenesis of diabetic cardiomyopathy providing information regarding targets for therapeutic interventions that will aid in the treatment of type 1 diabetes mellitus. The genesis of therapeutic tools designed to treat specific mitochondrial subsets will enhance therapy option flexibility, and provide a better means for the treatment of loci at risk from diabetes mellitus.

项目摘要 /摘要 在美国，有1-200万人患有1型糖尿病。糖尿病心肌病是 独立于冠状动脉疾病而存在的心肌障碍，与 糖尿病。糖尿病心肌病的特征是收缩功能障碍，有助于 心肌梗塞和心力衰竭。与糖尿病有关的高血糖，增加反应性 氧（ROS）产生。因为线粒体是ROS生成的主要位置，所以 确定线粒体如何受糖尿病的影响对于理解 发病。两个线粒体亚群的检查使线粒体的检查变得复杂 存在于心肌细胞，纤维中线粒体（IFM）中，该线粒体位于收缩之间 质膜下方存在的设备和肾小管线粒体（SSM）。目前，是 尚不清楚糖尿病在空间上不同的线粒体亚群如何使其困难 确定它们对糖尿病心肌病的特定贡献。我们的长期目标是阐明 糖尿病心肌病的发病机理涉及的机制是发展的先决条件 旨在减少与糖尿病有关的心脏并发症的治疗剂。中央 该应用的假设是心脏IFM比SSM更大的糖尿病侮辱风险。这 该应用程序的目标是确定糖尿病侮辱对空间不同的线粒体的影响 亚群，确定导致特定线粒体亚群功能障碍的关键因素，以及 开发靶向空间不同的线粒体子集的治疗剂。 公共卫生相关声明 拟议的研究将增强我们对糖尿病心肌病的发病机理的理解 提供有关治疗干预措施目标的信息，以帮助治疗1型 糖尿病。旨在治疗特定线粒体子集的治疗工具的起源将 增强治疗选择的灵活性，并为糖尿病风险的基因座提供更好的手段 Mellitus。