Mechanisms of Diabetic Cardiomyopathy: Mitochondria Subpopulations Brought to Foc

项目概要/摘要 美国有一到两百万人患有 1 型糖尿病。糖尿病心肌病是 与冠状动脉疾病无关且与以下疾病相关的心肌损伤 糖尿病。糖尿病心肌病的特点是收缩功能障碍，导致 心肌梗塞和心力衰竭。与糖尿病相关的高血糖会增加反应性 氧物质（ROS）的产生。因为线粒体是ROS产生的主要场所， 确定线粒体如何受糖尿病影响对于理解糖尿病至关重要 发病机制。线粒体的检查很复杂，因为两个线粒体亚群 存在于心肌细胞中，纤维间线粒体（IFM），位于收缩肌之间 存在于质膜下方的装置和肌膜下线粒体（SSM）。目前，它是 尚不清楚糖尿病如何影响空间上不同的线粒体亚群，这使得研究变得困难 以确定它们对糖尿病心肌病的具体贡献。我们的长期目标是阐明 糖尿病心肌病发病机制是糖尿病心肌病发生的先决条件 旨在减少与糖尿病相关的心脏并发症的疗法。中央 该应用的假设是心脏 IFM 比 SSM 遭受糖尿病损伤的风险更大。的 本申请的目的是确定糖尿病损伤对空间上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 开发针对空间上不同的线粒体亚群的疗法。 公共卫生相关性声明 拟议的研究将增强我们对糖尿病心肌病发病机制的理解 提供有关有助于治疗 1 型疾病的治疗干预目标的信息 糖尿病。旨在治疗特定线粒体亚群的治疗工具的起源将 增强治疗选择的灵活性，为治疗糖尿病风险位点提供更好的手段 梅利图斯。

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.