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.

尽管心脏病的发病率总体上有所下降，但发生心力衰竭的风险增加， 在糖尿病患者中仍然高出两倍。来自我们实验室和其他机构的证据表明， 发现葡萄糖水平和摄取的波动直接导致心血管疾病 (CVD)通过改变蛋白质、DNA和基因表达。在葡萄糖的情况下，临床研究 显示在严格血糖控制后，疾病进展的易感性持续数年或 甚至数十年的血糖记忆。我们实验室的长期目标是 了解葡萄糖在血糖记忆形成中的作用，并确定这些变化是否 改变疾病进展。最近，表观遗传调控的机制，其中包括 帮助包装DNA和直接修饰DNA的组蛋白蛋白修饰（例如 甲基化），与血糖记忆有关。决定分子水平的一个关键障碍 机制是能够将标记放置在完整的心脏中以测试疾病易感性。 在过去的2-5年里，有两个新的进展， 翻译后修饰，O-GlcNAcylation，处于这一探索的最前沿。具体来说，O- GlcNAc化是组蛋白密码的一部分。其次，调节O-GlcNAc酰化的蛋白质 与定制DNA甲基化的蛋白质相互作用，提供葡萄糖和葡萄糖之间的第二个联系。 表观遗传学本提案的目的是确定一种机制， 葡萄糖的波动改变DNA甲基化，以及这些变化如何改变基因表达， 心脏功能由于糖尿病和心力衰竭是具有强烈代谢成分的疾病，我们 将集中在葡萄糖介导的表观遗传变化如何改变代谢和能量学， 心脏病我们已经开发了两种新的小鼠模型来验证这一假设。第一次建造 在我们的葡萄糖转运蛋白，GLUT 4， 第二个是心肌细胞O-GlcNAc调节的新模型。因此，我们可以 直接测试心肌细胞葡萄糖递送和GlcNAc化在CVD中的作用。我们 初步数据定义了持续的DNA甲基化变化，增加了对压力的敏感性- 超负荷肥大在这项提案中，我们将：确定改变DNA甲基化的机制 (Aim 1），确定这些表观遗传修饰是否改变了收缩和代谢功能障碍， 对常见糖尿病合并高血压的反应（目的2），并确定O-GlcNAc 单独使用足以增加疾病易感性（目的3）。总的来说，完成这些 这些研究将为葡萄糖在调节 心脏基因表达促进糖尿病CVD的发展。