Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes

糖尿病期间心脏自噬的异常昼夜节律调节

• 批准号: 10078980
• 负责人: JOHN C CHATHAM
• 金额: $ 48.11万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078980
• 关键词: Adverse event; Animals; Attenuated; Autophagocytosis; Behavior; Behavioral; Cardiac; Cardiac Myocytes; Cardiac development; Cardiovascular system; Cell Respiration; Chronic; Circadian Dysregulation; Clock protein; Development; Diabetes Mellitus; Dilated Cardiomyopathy; Eating; Etiology; Exhibits; Genetic; Genetic Transcription; Heart; Heart failure; Housekeeping; Human; Impairment; Intervention; Investigation; Laboratories; Link; Maintenance; Mediating; Mediator of activation protein; Mitochondria; Modeling; Myocardial Infarction; Myocardial dysfunction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Phase; Physiological; Play; Post-Translational Protein Processing; Post-Translational Regulation; Process; Property; Proteins; Quality Control; Risk; Risk Factors; Role; Secondary to; Sleep; Sleep Deprivation; Testing; Therapeutic; Time; Transcriptional Regulation; Variant; Workload; awake; base; cardiovascular disorder risk; cell injury; circadian; circadian pacemaker; circadian regulation; diabetic; diabetic cardiomyopathy; diabetic patient; extracellular; glucose metabolism; heart function; innovation; insight; meetings; mitochondrial autophagy; mortality; preservation; repaired; shift work

Numerous mechanisms have been proposed as contributing factors in the etiology of diabetic cardiomyopathy, ranging from neurohumoral imbalances and extracellular remodeling, to perturbations in the intrinsic properties of cardiomyocytes. In the latter case, imbalances in rates of damage (e.g., oxidative) and replacement (i.e., turnover) of cellular constituents (e.g., proteins, mitochondria) have been implicated in the development of cardiac dysfunction during diabetes. Although many studies have investigated the role of increased oxidative stress, little is known regarding how diabetes impairs the turnover of damaged cellular constituents. Turnover of cellular constituents exhibits a striking time-of-day-dependent variation, which is governed by the cardiomyocyte circadian clock. Moreover, genetic disruption of the clock in the heart temporally suspends these processes, leading to development of dilated cardiomyopathy. Compelling evidence presented within this application suggests that both autophagy and mitophagy (autophagy of mitochondria), processes critical in the repair/replacement of cellular constituents, are circadian regulated in the heart. Our investigation of the cardiomyocyte circadian clock further revealed that the posttranslational modification, protein O-GlcNAcylation, is integral to the clock mechanism; the importance of this relationship is highlighted during diabetes (both type 1 and 2), when chronic elevation of cardiac protein O-GlcNAcylation (secondary to aberrant glucose metabolism) is associated with a phase shift in the clock within the heart. We postulate therefore that disruption of the clock-O-GlcNAc relationship during diabetes causes temporal misalignment of cardiac processes involved in repair/replacement of cellular constituents. These studies have led to the hypothesis that chronic disruption of the clock-O-GlcNAc relationship in the heart during T2DM impairs temporal partitioning of autophagy/mitophagy, ultimately impairing cellular constituent quality control leading to contractile function. In order to test this hypothesis, three Specific Aims are proposed. Aim 1: Demonstrate that the cardiomyocyte circadian clock modulates quality control of cellular constituents through transcriptional and posttranslational regulation of autophagy/mitophagy mediators (Physiologic/Mechanistic Aim). Aim 2: Demonstrate that chronic disruption of the clock-O- GlcNAc relationship during T2DM impairs quality control of cellular constituents through attenuated temporal partitioning of autophagy/mitophagy (Pathologic Aim). Aim 3: Demonstrate that behavior- and/or pharmacologic- mediated normalization of the clock-O-GlcNAc relationship during T2DM attenuates development of cardiac dysfunction (Therapeutic Aim). Successful completion of the proposed studies will lead to new fundamental insights regarding the causal role of circadian disruption in the etiology of diabetic cardiomyopathy, and will help identify innovative approaches for reducing the risk of cardiac dysfunction in diabetic patients.

已经提出了许多机制作为糖尿病心肌病病因的促成因素， 从神经肿瘤失衡和细胞外重塑到内在特性的扰动 心肌细胞。在后一种情况下，损害率不平衡（例如氧化）和更换（即 细胞成分的周转率（例如蛋白质，线粒体）与发展有关 糖尿病期间的心脏功能障碍。尽管许多研究研究了氧化增加的作用 压力，关于糖尿病如何损害受损细胞成分的营业额，几乎不知道。 细胞成分的营业额表现出惊人的日期依赖性变化，该变化受 心肌细胞昼夜节律。此外，心脏中时钟的遗传破坏在时间上暂停 这些过程，导致扩张心肌病的发展。内部提出的令人信服的证据 该应用表明自噬和线粒体（线粒体的自噬）都在处理至关重要的过程中 细胞成分的修复/置换是在心脏中调节的昼夜节律。我们对 心肌细胞昼夜节律进一步表明，翻译后修饰，蛋白O-Glcnacylation， 是时钟机制不可或缺的；糖尿病期间突出了这种关系的重要性（两种类型 1和2），当心脏蛋白O-Glcnacylation的慢性升高（继发于异常葡萄糖 代谢）与心脏内时钟的相移有关。因此，我们假设 糖尿病期间时钟O-GLCNAC关系的破坏会导致时间不对。 涉及细胞成分修复/替代的心脏过程。这些研究导致了 假设T2DM期间，心脏中时钟O-GLCNAC关系的慢性破坏 损害自噬/线粒体的时间分配，最终会损害细胞成分的质量 控制导致收缩功能。为了检验这一假设，提出了三个具体目标。 目标1：证明心肌细胞昼夜节律时钟调节细胞的质量控制 通过转录和翻译后的自噬/线粒体调节的成分 介体（生理/机械目的）。目的2：证明时钟O-的慢性破坏 T2DM期间的GlcNAC关系损害了细胞成分的质量控制 自噬/线粒体的时间分配（病理目标）。目标3：证明这种行为 - T2DM期间时钟O-GLCNAC关系的药理 - 介导的归一化 减弱心脏功能障碍的发展（治疗目标）。成功完成 拟议的研究将导致有关昼夜节律在因果关系中的作用的新基本见解 糖尿病性心肌病的病因，将有助于确定降低心脏风险的创新方法 糖尿病患者功能障碍。