Suppression of Autophagy-Dependent Clearance Mitochondria in Type 2 Diabetes

2 型糖尿病中自噬依赖性清除线粒体的抑制

• 批准号: 9032528
• 负责人: Zhonglin Xie
• 金额: $ 61.31万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032528
• 关键词: Acetylation; Affect; Animal Model; Apoptosis; Apoptotic; Attenuated; Autophagocytosis; Biogenesis; CASP8 gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Survival; Cultured Cells; Data; Deacetylation; Development; Diabetes Mellitus; Diabetic mouse; Disease; Down-Regulation; Event; Excision; Fatty Acids; Genes; Health; Heart; Heart failure; Heterozygote; High Fat Diet; Homeostasis; Homozygote; Hyperglycemia; Insulin Resistance; Knockout Mice; Leptin; Mediating; Mitochondria; Mus; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; PPAR gamma; PTEN-induced putative kinase; Pathologic Processes; Pathway interactions; Patients; Production; Protein Kinase; Proteins; Reactive Oxygen Species; Resveratrol; Risk Factors; Signal Pathway; Signal Transduction; Sirolimus; Source; Testing; United States; diabetic; diabetic cardiomyopathy; diabetic patient; feeding; improved; insight; loss of function; mitochondrial autophagy; multidisciplinary; novel strategies; overexpression; prevent; promoter; therapeutic target; translational approach

 DESCRIPTION (provided by applicant): Mitochondria are essential for energy production, but, if damaged, they become a major source of reactive oxygen species (ROS) and proapoptotic factors. Selective removal of dysfunctional mitochondria via autophagy is therefore an important mechanism to maintain mitochondrial function and preserve cell viability. Our exciting preliminary data suggests that autophagy is suppressed and damaged mitochondria are accumulated in diabetic heart, both of which contribute to cardiomyocyte apoptosis and cardiac dysfunction in Type 2 diabetic hearts. The central hypothesis of this proposal is that reduced Sirtuin 1 activity -mediated deacetylation of FoxO1 in Type 2 diabetic hearts suppresses autophagic clearance of dysfunctional mitochondria, leading to cardiomyopathy by accentuating cardiomyocyte apoptosis through p62-dependent activation of caspase-8 and/or mitochondrial ROS. This hypothesis will be tested by using gain-/loss-of function strategies in both animal models and cultured cells. Aim 1 is to establish if defective autophagy-dependent mitochondrial clearance causes cardiac structural and functional damages in diabetes and if so, delineate the mechanism of action. In this Aim, we will test the hypothesis that defective mitochondrial autophagy causes cardiomyopathy by potentiating cardiomyocyte apoptosis through p62- dependent activation of caspase-8 and/or mitochondrial ROS in Type 2 diabetes. Aim 2 is to elucidate how mitochondrial autophagy becomes impaired in diabetic heart. We will determine whether diabetes-inhibited Sirtuin 1 signaling results in suppression of mitochondrial autophagy through down-regulation of PINK1 and Beclin1. The proposed studies will provide new insights into how diabetes induces cardiomyopathy and the modulation of autophagy via stimulation of SIRT1-FoxO1 signaling is a therapeutic target to prevent or delay cardiomyopathy in diabetes.

 描述（由适用提供）：线粒体对于能源生产至关重要，但是，如果损坏，它们成为活性氧（ROS）和促凋亡因子的主要来源。因此，通过自噬选择性去除功能失调的线粒体是维持线粒体功能并保持细胞活力的重要机制。我们令人兴奋的初步数据表明，自噬被抑制，线粒体会累积在糖尿病心脏中，这两种糖尿病心脏的心肌细胞凋亡和心脏功能障碍在2型糖尿病心脏中有助于。该提议的中心假设是，在2型糖尿病心脏中，Sirtuin 1活性介导的FOXO1的脱乙酰基化抑制了通过caspase-8和/或Mitococycycytrial Ros的p62依赖性激活功能障碍线粒体凋亡的自噬清除。该假设将通过在动物模型和培养细胞中使用 - 功能损失策略来检验。目的1是确定有缺陷的自噬依赖性线粒体清除是否会导致糖尿病中的心脏结构和功能损害，如果是的，则描述了作用机理。在此目标中，我们将检验以下假设：有缺陷的线粒体自噬通过通过p62依赖性激活caspase-8和/或线粒体ROS在2型2型糖尿病中增强心肌细胞凋亡，从而导致心肌病。目的2是阐明线粒体自噬如何在糖尿病心脏中受损。我们将通过下调PINK1和BECLIN1的下调来确定糖尿病是否受到抑制SIRTUIN 1信号传导导致线粒体自噬的抑制。拟议的研究将提供有关糖尿病如何诱导心肌病的新见解，以及通过刺激SIRT1-FOXO1信号传导对自噬的调节是预防或延迟糖尿病中心肌病的治疗靶点。