Mechanisms of Diabetic Cardiomyopathy: Mitochondria Subpopulations Brought to Foc

项目摘要/摘要 在美国，有一两百万人患有1型糖尿病。糖尿病心肌病是 一种独立于冠状动脉疾病而存在的心肌损伤，与 糖尿病。糖尿病心肌病的特征是收缩功能障碍，这有助于 心肌梗塞和心力衰竭。高血糖与糖尿病相关，增加反应性 氧物种(ROS)的产生。因为线粒体是产生ROS的主要部位， 确定线粒体是如何受到糖尿病影响的对于理解糖尿病是至关重要的 发病机制。线粒体的检查由于两个线粒体亚群的事实而变得复杂 存在于心肌细胞中，即纤维间线粒体(IFM)，它位于收缩之间 细胞器和肌膜下线粒体(SSM)存在于质膜之下。目前，它是 目前尚不清楚糖尿病如何影响空间上不同的线粒体亚群，从而使研究变得困难 以确定它们在糖尿病心肌病中的具体作用。我们的长期目标是澄清 糖尿病心肌病的发病机制是糖尿病发生发展的先决条件 旨在减少与糖尿病相关的心脏并发症的治疗。中环 这一应用的假设是心脏IFM比SSM更容易患糖尿病。这个 这项应用的目的是确定糖尿病损害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 开发针对空间不同线粒体亚群的治疗方法。 公共卫生相关声明 建议的研究将加深我们对糖尿病心肌病发病机制的理解。 提供有关将有助于1型糖尿病治疗的治疗干预目标的信息 糖尿病。设计用于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，为糖尿病高危基因座的治疗提供更好的手段 糖尿病。

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.