Protein O-GlcNAcylation and the regulation of cardiac function

描述（由申请人提供）：众所周知，糖尿病导致心力衰竭发生的风险显著增加，独立于其他危险因素；然而，对于所涉及的机制或最适当的治疗策略尚无共识。ss- n -乙酰氨基葡萄糖（O-GlcNAc）与丝氨酸和苏氨酸残基的o键连接是细胞核和细胞质蛋白翻译后的高度动态修饰。这种新颖的代谢调节信号通路正在成为关键生物过程的关键调节因子，o - glcn酰化的持续增加与糖尿病相关的心血管并发症有关。相反，最近的研究表明，O-GlcNAc水平的急性激活可以防止缺氧和缺血应激。然而，尽管我们越来越认识到o - glcn酰化在介导心肌细胞对急性和慢性应激反应中的重要性，但对于o - glcn酰化在调节正常心肌细胞功能中的基本作用知之甚少。因此，在我们初步研究的基础上，本课题的目标是验证以下假设：1)正常心脏中o - glcnnac蛋白酰化参与心肌细胞基因表达、代谢和自噬的调节；2)o - glcnnac合成和降解的失调导致糖尿病对心脏的不良影响，包括基因表达改变、代谢功能障碍和自噬反应受损。因此，本提案的目的是确定o - glcn酰化在以下方面的作用：1)心肌细胞基因表达的调节以及2型糖尿病如何改变心肌细胞基因表达，并鉴定易受O-GlcNAc水平急性和慢性变化影响的O-GlcNAc修饰的心肌细胞蛋白；2)正常和2型糖尿病小鼠心脏代谢的急、慢性调节，确定调节心脏O- GlcNAc转换的代谢因子；3)调节正常和2型糖尿病心肌细胞自噬和凋亡之间的平衡。这项研究的成功完成将大大提高我们对这种新的代谢介导的信号通路在正常情况下对心肌细胞功能的影响的理解，以及蛋白质O- glcn酰化失调如何导致糖尿病对心脏的不良影响。因此，这一应用的结果将是关于o - glcn酰化蛋白对心肌生理和病理生理影响的新的机制见解，潜在地确定新的治疗靶点。

DESCRIPTION (provided by applicant): It is well established that diabetes leads to a marked increased risk for the development of heart failure independent of other risk factors; however, there is no consensus as to the mechanisms involved or the most appropriate treatment strategies. The O-linked attachment of ss-N-acetyl- glucosamine (O-GlcNAc) to serine and threonine residues is a highly dynamic post-translational modification of nuclear and cytoplasmic proteins. This novel, metabolically regulated signaling pathway is emerging as a key regulator of critical biological processes and sustained increases in O-GlcNAcylation have been linked to the cardiovascular complications associated with diabetes. Conversely, recent studies have shown that acute activation of O-GlcNAc levels protects against hypoxic and ischemic stress. However, despite our increasing appreciation for the significance of O-GlcNAcylation in mediating the response of cardiomyocytes to acute and chronic stress, little is known regarding the fundamental role of O-GlcNAcylation in regulating normal cardiomyocyte function. Therefore, based on our preliminary studies the goal of this proposal is to test the following hypotheses: 1) In the normal heart protein O-GlcNAcylation contributes to regulation of cardiomyocyte gene expression, metabolism and autophagy and 2) Dysregulation in O-GlcNAc synthesis and degradation contribute to the adverse effects of diabetes on the heart including altered gene expression, metabolic dysfunction and impaired autophagic response. Thus the aims of this proposal are to determine the role of O-GlcNAcylation in: 1) The regulation of cardiomyocyte gene expression and e how this is altered in response to type-2 diabetes and identify O-GlcNAc modified cardiomyocyte proteins that are susceptible to acute and chronic changes in O-GlcNAc levels; 2) Acute and chronic regulation of cardiac metabolism and identify the metabolic factors involved in regulating O- GlcNAc turnover in hearts from normal and type-2 diabetic mice; 3) Mediating the balance between cardiomyocyte autophagy and apoptosis in normal and type-2 diabetic cardiomyocytes. The successful completion of the studies outlined in this proposal will significantly enhance our understanding of the impact of this novel metabolically mediated signaling pathway on the cardiomyocyte function under normal conditions as well as how dysregulation in protein O- GlcNAcylation contributes to adverse effects of diabetes on the heart. Consequently, the outcome of this application will be novel mechanistic insights regarding the influence of protein O-GlcNAcylation on myocardial physiology and pathophysiology, potentially identifying novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Although the there have been tremendous advances in treatment of cardiovascular disease; diabetic patients remain at substantially increased risk in for developing heart failure and dying from cardiac disease than non-diabetic patients. The overall goal of this project is to examine how changes in a newly identified modification of proteins, which is regulated in large part by glucose metabolism, affects the function of heart cells also known as cardiomyocytes. The outcome of this project will provide new insights into the detrimental effects of diabetes on the heart, potentially identifying of new approaches for treating diabetic patients with heart disease.