FUNDC1 and diabetic cardiomyopathy

FUNDC1 与糖尿病心肌病

• 批准号: 9332944
• 负责人: Zhonglin Xie
• 金额: $ 70.5万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332944
• 关键词: Ablation; Affect; Animal Model; Apoptotic; Attenuated; Binding Proteins; Calcium; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cessation of life; Data; Development; Diabetes Mellitus; Diabetic mouse; Endoplasmic Reticulum; Event; Friend Murine Leukemia Virus; Functional disorder; Genes; Genetic; Heart; Heart failure; Heterozygote; High Fat Diet; Homeostasis; Homozygote; ITPR1 gene; Impairment; Inositol; Knock-out; Knockout Mice; Leptin; Mediating; Membrane; Membrane Proteins; Mitochondria; Modeling; Molecular; Mus; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Outer Mitochondrial Membrane; Pathogenesis; Pathologic Processes; Pharmacology; Production; Protein Sortings; Proteins; Reactive Oxygen Species; Reticulum; Risk Factors; Role; Source; Streptozocin; Structural Protein; Structure; Testing; Up-Regulation; Work; diabetic; diabetic cardiomyopathy; diabetic patient; effective therapy; human disease; improved; in vivo; innovation; insight; loss of function; mitochondrial dysfunction; mouse model; non-diabetic; overexpression; prevent; receptor; type I diabetic

Project Summary Mitochondria are essential for energy production, but, if damaged, they become a major source of reactive oxygen species and proapoptotic factors. Increasing evidence suggests that mitochondrial dysfunction is a central event in the development of diabetic cardiomyopathy. However, the molecular mechanisms responsible for diabetes-caused mitochondrial dysfunction in cadiomyocytes remain poorly characterized. Our exciting preliminary data included in this application show that the levels of the FUN14 domain containing 1 (FUNDC1) protein, a mitochondrial outer-membrane protein, are highly increased in diabetic hearts resulting in mitochondrial dysfunction and diabetic cardiomyopathy. Mechanistically, aberrant FUNDC1 expression in diabetes increases endoplamsmic reticulum (ER)- mitochondria contact, which promotes Ca2+ transfer from the ER to the mitochondria and thus results in mitochondrial Ca2+ overload, cardiomyocyte death, and cardiac dysfunction. Cardiac-specific deletion of FUNDC1 reduces ER-mitochondria contacts, attenuating cardiac dysfunction in Type I and Type II diabetic mice. Thus, the central hypothesis of this proposal is that aberrant FUNDC1 expression in diabetes leads to cardiomyopathy by impairing mitochondrial function through enhancement of ER-mitochondria contacts. This hypothesis will be tested by using gain-/loss-of function and pharmacologic/genetic strategies in both animal models and cultured cardiomyocytes. Aim 1 is to establish the essential roles of increased FUNDC1 expression in the development of diabetic cardiomyopathy. In this Aim, we will test the hypotheis that enhanced FUNDC1 expression causes cardiac structural damage and dysfunction by compromising mitochondrial function in diabetes. Aim 2 is to elucidate the mechanism by which FUNDC1 upregulation in diabetes impairs mitochondrial function, leading to cardiomyopathy. In this aim, we will test the hypothesis that diabetes-enhanced FUNDC1 expression impairs mitochondrial function by promoting the ER- mitochondria contacts. We will determine if FUNDC1 mediates ER-mitochondria contacts in diabetic hearts, investigate whether increased FUNDC1 causes mitochondrial dysfunction and cardiomyocyte death by increasing Ca2+ transfer from ER to mitochondria, and examine whether diminishing ER- mitochondrial Ca2+ flux improves mitochondrial and cardiac function in diabetic hearts using IP3R2 cardiomyocyte-specific knockout mice. The completion of this highly innovative proposal will help develop a new paradigm for treating diabetic cardiomyopathy.

项目概要 线粒体对于能量产生至关重要，但如果受损，它们就会成为能量的主要来源 活性氧和促凋亡因子。越来越多的证据表明线粒体 功能障碍是糖尿病心肌病发展的核心事件。然而，分子 糖尿病导致心肌细胞线粒体功能障碍的机制仍然存在 特征不佳。我们在此应用程序中包含的令人兴奋的初步数据表明， FUN14 结构域包含 1 (FUNDC1) 蛋白，一种线粒体外膜蛋白，是 糖尿病心脏中的线粒体高度增加，导致线粒体功能障碍和糖尿病心肌病。 从机制上讲，糖尿病中 FUNDC1 的异常表达会增加内质网 (ER) - 线粒体接触，促进 Ca2+ 从内质网转移到线粒体，从而产生 线粒体 Ca2+ 超载、心肌细胞死亡和心功能障碍。心脏专用 FUNDC1 缺失减少了 ER 线粒体接触，减轻了 I 型和 II型糖尿病小鼠。因此，该提案的中心假设是异常的 FUNDC1 糖尿病中的表达通过损害线粒体功能导致心肌病 ER-线粒体接触的增强。该假设将通过使用增益/损失来检验 动物模型和培养心肌细胞的功能和药理学/遗传策略。 目标 1 是确定 FUNDC1 表达增加在发育中的重要作用 糖尿病心肌病。在这个目标中，我们将测试增强 FUNDC1 表达的假设 通过损害线粒体功能导致心脏结构损伤和功能障碍 糖尿病。目标 2 是阐明糖尿病中 FUNDC1 上调损害的机制 线粒体功能受损，导致心肌病。为了这个目标，我们将检验以下假设： 糖尿病增强的 FUNDC1 表达通过促进 ER- 损害线粒体功能 线粒体接触。我们将确定 FUNDC1 是否介导糖尿病患者的 ER-线粒体接触 心脏，调查 FUNDC1 增加是否会导致线粒体功能障碍和心肌细胞 通过增加 Ca2+ 从 ER 到线粒体的转移来死亡，并检查是否减少 ER- 使用 IP3R2 线粒体 Ca2+ 通量改善糖尿病心脏的线粒体和心脏功能 心肌细胞特异性基因敲除小鼠。这一极具创新性的提案的完成将有助于 开发治疗糖尿病心肌病的新范例。