FUNDC1 and diabetic cardiomyopathy

FUNDC1 与糖尿病心肌病

基本信息

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
项目类别：
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

项目摘要

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增强内质网-线粒体接触。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。