Glucose-Mediated Remodeling of Cardiac DNA Methylation

葡萄糖介导的心脏 DNA 甲基化重塑

• 批准号: 9767852
• 负责人: Adam Raymond Wende
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767852
• 关键词: Adherence; Adverse effects; Animals; Automobile Driving; Binding; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Chromatin; Clinical Research; Comorbidity; DNA; DNA Methylation; DNA Methylation Regulation; DNA Modification Process; Data; Development; Diabetes Mellitus; Diet; Dioxygenases; Disease; Disease Progression; Disease susceptibility; Dominant-Negative Mutation; Epigenetic Process; Excision; Exercise; Exposure to; Foundations; Functional disorder; GLUT4 gene; Gene Expression; Gene Expression Regulation; Glucose; Glucose Transporter; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; High Prevalence; Histone Code; Human; Hypertension; Hypertrophy; Insulin-Dependent Diabetes Mellitus; Intervention; Knowledge; Laboratories; Lead; Link; Mediating; Memory; Metabolic; Metabolic dysfunction; Metabolism; Methylation; Mitochondria; Modeling; Modification; Molecular; Mus; Myocardial dysfunction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; O-GlcNAc transferase; Pathway interactions; Patients; Pharmacologic Substance; Post-Translational Protein Processing; Predisposition; Process; Proteins; Recording of previous events; Regulation; Risk; Role; Secondary to; Signal Transduction; Stress; Testing; Time; Transcript; blood glucose regulation; constriction; diabetic; diabetic cardiomyopathy; epigenetic regulation; epigenome; glucose uptake; glycemic control; glycosylation; heart disease risk; heart function; hemodynamics; histone modification; in vivo; insight; methylation pattern; mouse model; novel; overexpression; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; pressure; response; uptake

Despite overall reductions in heart disease, the increased risk of developing heart failure has remained 2-fold greater among people with diabetes. Evidence from our laboratory and others has identified that fluctuations in glucose level and uptake directly contributes to cardiovascular disease (CVD) by modifying proteins, DNA, and gene expression. In the case of glucose, clinical studies have shown that following tight glycemic control, susceptibility to disease progression is sustained years or even decades in a process termed “glycemic memory”. A long-term goal of our laboratory is to understand the role of glucose in the formation of glycemic memory and determine if these changes alter disease progression. Recently the mechanism of epigenetic regulation, which consists of modifications of the histone proteins that help package DNA and direct modifications of the DNA (e.g. methylation), is linked to glycemic memory. A critical barrier in determining the molecular mechanisms has been the ability to place the marks in the intact heart to test disease susceptibility. Two novel advances have taken place over the last 2-5 years that place the glucose-mediated protein post-translational modification, O-GlcNAcylation, at the forefront of this quest. Specifically, O- GlcNAcylation is part of the histone code. Secondly, the proteins that regulate O-GlcNAcylation interact with the proteins that tailor DNA methylation, providing a second link between glucose and epigenetics. The objective of the current proposal is to determine the mechanism by which fluctuations in glucose alter DNA methylation and how these changes alter gene expression and cardiac function. As diabetes and heart failure are diseases with strong metabolic components, we will focus on how glucose-mediated epigenetic changes alter metabolism and energetics in acquired heart disease. We have developed two novel mouse models to test this hypothesis. The first builds upon our model of inducible cardiomyocyte-specific expression of the glucose transporter, GLUT4, and the second is a new model of cardiomyocyte O-GlcNAc regulation. Thus uniquely allowing us to directly test the role that cardiomyocyte glucose delivery and GlcNAcylation have on CVD. Our preliminary data define persistent DNA methylation changes that increase susceptibility to pressure- overload hypertrophy. In this proposal we will: determine the mechanism of altered DNA methylation (Aim 1), determine if these epigenetic modifications alter contractile and metabolic dysfunction in response to a common diabetic co-morbidity of hypertension (Aim 2), and determine if O-GlcNAc alone is sufficient to increase disease susceptibility (Aim 3). Collectively, the completion of these studies will provide fundamental insights into the mechanistic basis for glucose in the regulation of cardiac gene expression contributing to the development of diabetic CVD.

尽管心脏病的总体降低，但心力衰竭的风险增加已经 在糖尿病患者中恢复了2倍。 确定波动水平和吸收直接导致心血管疾病 （CVD）通过修饰蛋白质，DNA和基因表达。 表明，在严重的血糖控制之后，疾病进展的敏感性是持续的一年 即使在一个被称为“血糖记忆”的过程中，甚至几十年。 了解葡萄糖在形成血糖记忆中的作用，并确定这些变化是否发生变化 改变疾病的进展。 组蛋白的修饰有助于包装DNA和DNA的直接修饰（例如 甲基化），与确定分子的关键障碍有关 机制已经放置于to骨心脏疾病的疾病。 在过去的2 - 5年中，已有两个新的进步，将葡萄糖介导的蛋白 在此任务的最前沿，转化后修改，O-Glcnacylation。 Glcnacylation是组蛋白代码的一部分。 与量身定制DNA甲基化的蛋白质相互作用，在葡萄糖和 表观遗传学。 葡萄糖改变的波动以及如何改变基因表达和 心脏功能作为糖尿病和心力衰竭是具有强大代谢成分的疾病 将重点介绍葡萄糖介导的表观遗传变化如何改变获得的代谢和能量学 心脏病 根据我们的诱导型心肌细胞特异性表达的模型，葡萄糖转运蛋白glut4， 第二个是心肌细胞O-GLCNAC评论的新模型。 直接测试心肌细胞葡萄糖递送和Glcncylation对CVD的作用 初步数据定义了持续的DNA甲基化变化，从而增加了压力的敏感性 超负荷肥大。 （AIM 1），确定这些表观遗传修饰是否会改变收缩和代谢功能障碍 对高血压的常见糖尿病联合糖果（AIM 2）的反应，并确定O-GLCNAC是否 仅是增加疾病的补充（AIM 3）。 研究将为调节葡萄糖的机械基础提供基本见解 心脏基因表达有助于糖尿病CVD的发展。