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（由申请人提供）：线粒体对于能量产生至关重要，但如果受损，它们就会成为活性氧（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和保持细胞活力的重要机制。我们令人兴奋的初步数据表明，糖尿病心脏中自噬受到抑制，受损线粒体积累，这两者都会导致 2 型糖尿病心脏中的心肌细胞凋亡和心功能障碍。该提议的中心假设是，2 型糖尿病心脏中 Sirtuin 1 活性降低介导的 FoxO1 脱乙酰化会抑制功能失调的线粒体的自噬清除，通过 p62 依赖性的 caspase-8 和/或线粒体 ROS 激活，加剧心肌细胞凋亡，从而导致心肌病。该假设将通过在动物模型和培养细胞中使用功能获得/丧失策略来检验。目标 1 是确定自噬依赖性线粒体清除缺陷是否会导致糖尿病患者的心脏结构和功能损伤，如果是的话，请描述其作用机制。在这个目标中，我们将检验以下假设：在 2 型糖尿病中，线粒体自噬缺陷通过 p62 依赖性的 caspase-8 和/或线粒体 ROS 激活，增强心肌细胞凋亡，从而导致心肌病。目标 2 是阐明糖尿病心脏中线粒体自噬如何受损。我们将确定糖尿病抑制的 Sirtuin 1 信号传导是否会通过下调 PINK1 和 Beclin1 来抑制线粒体自噬。拟议的研究将为糖尿病如何诱发心肌病提供新的见解，并且通过刺激 SIRT1-FoxO1 信号传导调节自噬是预防或延缓糖尿病心肌病的治疗靶标。