Disruption of the Clock O-GlcNAc axis in diabetic cardiomyopathy

糖尿病心肌病中时钟 O-GlcNAc 轴的破坏

• 批准号: 8814019
• 负责人: JOHN C CHATHAM
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-03 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814019
• 关键词: ARNT gene; Acute; Adverse effects; Age of Onset; Attenuated; Brain; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cells; Circadian Rhythms; Clinical Treatment; Dependence; Development; Diabetes Mellitus; Disease Progression; Etiology; Event; Exhibits; Functional disorder; Gap Junctions; Genetic; Genetic Transcription; Goals; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Ischemia; Knock-out; Knockout Mice; Knowledge; Lead; Link; Longevity; Mediating; Metabolism; Modeling; Molecular; Muscle; Myocardial dysfunction; Myocardium; Organ; Outcome Study; Output; Pathologic; Pathology; Patients; Phase; Phosphorylation; Physiology; Play; Post-Translational Protein Processing; Protein Biosynthesis; Proteins; Publishing; Reperfusion Therapy; Reporting; Risk; Risk Factors; Role; Signal Transduction; Stimulus; Testing; Time; Translations; cardiovascular disorder risk; circadian pacemaker; clinically relevant; diabetic; diabetic cardiomyopathy; diabetic patient; infancy; insight; mouse model; multicatalytic endopeptidase complex; mutant; novel; novel strategies; protein degradation; protein function; public health relevance; repaired; stressor; transcription factor

DESCRIPTION (provided by applicant): Diabetes remains a major risk factor for the development of both ischemic and non-ischemic cardiovascular disease (CVD); however, despite improvements in clinical treatments, our knowledge of the molecular underpinnings of diabetes-associated CVD is poorly understood. As with the majority of cardiovascular physiology, pathologic cardiovascular events exhibit a time-of-day-dependence, with regards to both onset and impact on disease progression and we have shown that the cardiomyocyte circadian clock directly influences the manner with which the heart responds to specific stressors. Importantly, we have shown that diabetes induces a phase shift in the cardiomyocyte circadian clock. Thus dysynchrony of the cardiomyocyte circadian clock may be an important and previously unrecognized contributor to the etiology of diabetic cardiomyopathy. Protein O-GlcNAcylation, a metabolically regulated post-translational modification that rapidly influences protein function, is increasingly recognized as a key regulator of both cardiac physiology and pathology including the adverse effects of diabetes. We recently reported that the cardiomyocyte circadian clock directly influences cardiac O-GlcNAc levels, that at least two circadian clock components are O-GlcNAc modified, and those acute increases in O-GlcNAc levels phase shifts the clock similarly to that seen in the heart during diabetes. We have also observed increased protein synthesis in the heart during the inactive phase, a time when protein O-GlcNAcylation is low. This has led us to postulate that protein O- GlcNAcylation may be a key mechanism by which the cardiomyocyte circadian clock temporally coordinates repair/replacement of damaged proteins in the heart. Collectively, these observations support the overall hypothesis of this proposal that dysregulation of protein O-GlcNAcylation is a critical factor contributing to diabetes-induced alterations of the cardiomyocyte circadian clock, and that misalignment of the cardiomyocyte circadian clock represents a key mechanism underlying diabetes-related cardiac dysfunction. To test this hypothesis we will pursue 3 specific aims: 1) Determine the molecular underpinnings linking the cardiomyocyte circadian clock with protein O-GlcNAcylation, and identify how this relationship is altered during diabetes; 2) Determine the role of O-GlcNAcylation in circadian clock mediated protein turnover, and elucidate how this relationship is modified during diabetes; 3) Determine whether re-alignment of the cardiomyocyte circadian clock during diabetes attenuates cardiomyopathy development. Successful completion of the proposed studies will lead to new fundamental insights regarding the molecular mechanisms underlying the role of aberrant circadian function in the development of diabetes-related cardiac disease and will help identify new approaches for reducing the risk of CVD in diabetic patients.

描述（由申请人提供）：糖尿病仍然是缺血性和非缺血性心血管疾病（CVD）发展的主要危险因素；然而，尽管临床治疗有所改善，但我们对糖尿病相关心血管疾病的分子基础知之甚少。与大多数心血管生理学一样，病理性心血管事件在发病和对疾病进展的影响方面表现出一天中的时间依赖性，我们已经证明心肌细胞生物钟直接影响心脏对特定压力源的反应方式。重要的是，我们已经证明糖尿病会引起心肌细胞生物钟的相移。因此，心肌细胞生物钟的不同步可能是糖尿病性心肌病病因学的一个重要的、以前未被认识到的因素。蛋白o - glcn酰化是一种代谢调节的翻译后修饰，可迅速影响蛋白质功能，越来越被认为是心脏生理和病理（包括糖尿病的不利影响）的关键调节因子。我们最近报道了心肌细胞生物钟直接影响心脏O-GlcNAc水平，至少有两个生物钟成分被O-GlcNAc修改，而O-GlcNAc水平的急性升高会使生物钟发生相移，这与糖尿病期间心脏的情况类似。我们还观察到，在无活性阶段，蛋白质o - glcn酰化水平较低，心脏中蛋白质合成增加。这使我们假设蛋白质O- glcn酰化可能是心肌细胞生物钟暂时协调心脏受损蛋白质修复/替换的关键机制。总的来说，这些观察结果支持了这一提议的总体假设，即蛋白质o - glcn酰化失调是一个关键因素