Aberrant Circadian Regulation of Autophagy in the Heart During Diabetes

在糖尿病心肌病的病因学中，许多机制被提出为促成因素， 从神经体液失衡和细胞外重构，到固有特性的扰动 心肌细胞。在后一种情况下，损伤率(例如，氧化)和更新率(即， 细胞成分(如蛋白质、线粒体)的周转)参与了 糖尿病期间的心脏功能障碍。尽管许多研究已经调查了增加氧化作用的作用 对于糖尿病如何损害受损细胞成分的周转，人们知之甚少。 细胞成分的周转表现出显著的时间依赖性变化，这是由 心肌细胞生物钟。此外，心脏生物钟的基因破坏会暂时暂停 这些过程，导致扩张型心肌病的发展。提供了令人信服的证据 这一应用表明，自噬和有丝分裂吞噬(线粒体的自噬)这两个过程在 细胞成分的修复/替换在心脏中受到昼夜节律的调节。我们对这一事件的调查 心肌细胞昼夜节律时钟进一步表明，翻译后修饰，蛋白质O-GlcN酰化， 是时钟机制的组成部分；这种关系的重要性在糖尿病(两种类型)期间都得到了强调 1和2)，当心脏蛋白O-GlcN酰化(继发于异常葡萄糖)慢性升高时 新陈代谢)与心脏内时钟的相移有关。因此，我们假定 糖尿病期间时钟-O-GlcNAc关系的中断导致时间错位 参与细胞成分修复/替换的心脏过程。这些研究导致了 T2 DM时心脏Clock-O-GlcNAc关系慢性紊乱的假说 损害自噬/有丝分裂的时间分割，最终损害细胞组成质量 控制导致收缩功能。为了验证这一假说，本文提出了三个具体目标。 目的1：证明心肌细胞昼夜节律时钟调节细胞质量控制 通过转录和翻译后调节自噬/有丝分裂吞噬的成分 中介者(生理学/机械学目标)。目标2：证明时钟-O-的慢性干扰 T2 DM期间GlcNAc关系通过衰减影响细胞成分的质量控制 自噬/有丝分裂的时间分割(病理目的)。目标3：证明行为-- 和/或药物介导的T2 DM时Clock-O-GlcNAc关系的正常化 延缓心脏功能障碍的发展(治疗目标)。圆满完成 拟议中的研究将导致对昼夜节律中断的因果作用的新的基本见解。 糖尿病心肌病的病因学，并将有助于确定降低心脏病风险的创新方法 糖尿病患者的功能障碍。

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.