O-GlcNAc Signaling in Heart Failure

心力衰竭中的 O-GlcNAc 信号传导

• 批准号: 8292161
• 负责人: Steven P Jones
• 金额: $ 36.49万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292161
• 关键词: Acetylglucosamine; Address; Affect; Biological; Biology; Cardiac; Cardiac Myocytes; Development; Disease Progression; Enzymes; Failure; Fostering; Functional disorder; Glucose; Goals; Growth; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hexosamines; Hypertrophy; Knockout Mice; Laboratories; Lead; Light; Link; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modification; Monosaccharides; Muscle Cells; Myocardium; Nuclear Proteins; O-GlcNAc transferase; Pathologic; Pathway interactions; Patients; Phenotype; Post-Translational Protein Processing; Proteins; Role; Series; Signal Pathway; Signal Transduction; Testing; Ventricular; design; in vivo; innovation; insight; novel; novel therapeutics; pressure; response

DESCRIPTION (provided by applicant): Cardiac hypertrophy arises from multiple, often idiopathic, origins. Pressure overload induces cardiomyocyte hypertrophy and eventually can lead to heart failure. The induction of pathologic hypertrophy involves the transcriptional reprogramming of metabolic machinery. Thus, hypertrophy involves a metabolic disturbance leading to cardiac dysfunction. Glucose represents the quintessential substrate for metabolism, albeit to a limited extent in the heart. Less than 5% of intracellular glucose is shunted to accessory pathways, such as Hexosamine Biosynthetic Pathway, which forms the monosaccharide donor for the post-translational modification known as O-linked-2-N- acetylglucosamine (O-GlcNAc). Many of the signaling pathways involved with the development of cardiac hypertrophy, particularly during the transition to failure, have been elegantly elucidated by other laboratories. The present proposal will unravel the contribution of O-GlcNAc signaling to the development of hypertrophy, in addition to understanding a potential role in pressure overload-induced heart failure. PGC-11 is recognized as a regulator of metabolism and its loss can aggravate pressure overload- induced heart failure. Nothing is currently known about the relationship between O-GlcNAc signaling and PGC-11 during the development of hypertrophy and heart failure. One goal of the present study is to investigate the mechanisms through which O-GlcNAc signaling participates in myocyte response to hypertrophy by focusing on the transcriptional activity of PGC-11. This proposal will identify the role O-GlcNAc signaling in the development of cardiomyocyte hypertrophy and heart failure by: 1) Determining what changes occur in O-GlcNAc signaling in the myocardium during hypertrophy. 2) Ascertaining whether O-GlcNAc signaling is essential during hypertrophy. 3) Identifying the influence of O-GlcNAc signaling on PGC-11 during hypertrophy. 4) Elucidating the impact of altered O-GlcNAc signaling at the mitochondrial level during hypertrophy. The PI's hypothesis is that O-GlcNAc signaling is augmented during the development of hypertrophy, and such augmentation of is maladaptive. Furthermore, the PI posits that O-GlcNAc signaling suppresses PGC-11, and, such changes are instrumental in the development of the hypertrophied and failing phenotypes. Findings from such mechanistic studies will provide novel insights into the pathophysiologic mechanisms operative during the development of hypertrophy and in the failing myocardium. PUBLIC HEALTH RELEVANCE: One limiting factor in identifying more efficacious treatments for heart failure is our lack of understanding of the initiation and progression of the disease, particularly as it relates to metabolic signaling. The present series of studies will provide keen insights into mechanisms of cardiac growth, metabolism, and the development of pressure overload induced hypertrophy, which will lay the groundwork for the creation of new therapeutics.

描述(申请人提供)：心肌肥大有多种原因，通常是特发性的。压力超负荷会导致心肌细胞肥大，最终导致心力衰竭。病理性肥大的诱导涉及代谢机制的转录重编程。因此，肥大涉及到导致心脏功能障碍的代谢紊乱。葡萄糖是新陈代谢的典型底物，尽管在心脏中的程度有限。只有不到5%的细胞内葡萄糖被分流到辅助途径，如己糖胺生物合成途径，这形成了翻译后修饰的单糖供体，称为O-连接-2-N-乙酰氨基葡萄糖(O-GlcNAc)。许多与心肌肥厚发展有关的信号通路，特别是在向衰竭的转变过程中，已经被其他实验室优雅地阐明。目前的建议将揭示O-GlcNAc信号在肥厚发展中的作用，以及在压力超负荷诱导的心力衰竭中的潜在作用。PGC-11被认为是一种新陈代谢调节剂，它的缺失会加重压力超负荷所致的心力衰竭。O-GlcNAc信号与PGC-11在肥厚和心力衰竭发生发展过程中的关系目前尚不清楚。本研究的目的之一是通过研究PGC-11的转录活性来研究O-GlcNAc信号参与心肌细胞肥大反应的机制。这项建议将通过以下几个方面确定O-GlcNAc信号在心肌肥大和心力衰竭发展中的作用：1)确定心肌肥厚过程中O-GlcNAc信号发生了什么变化。2)确定O-GlcNAc信号在肥厚过程中是否起重要作用。3)明确O-GlcNAc信号在肥大过程中对PGC-11的影响。4)阐明O-GlcNAc信号在线粒体水平的变化对肥大的影响。PI的假说是，O-GlcNAc信号在肥厚的发展过程中增强，这种增强是不适应的。此外，PI假设O-GlcNAc信号抑制PGC-11，这种变化有助于肥大和衰竭表型的发展。这些机制研究的结果将为肥厚发展和衰竭心肌的病理生理机制提供新的见解。公共卫生相关性：在寻找更有效的心力衰竭治疗方法方面，一个限制因素是我们对疾病的发生和发展缺乏了解，特别是当它与代谢信号有关时。这一系列的研究将对心脏生长、代谢和压力超负荷引起的肥厚的发展机制提供深刻的见解，这将为创造新的治疗方法奠定基础。