O-GlcNAc Signaling in Heart Failure

心力衰竭中的 O-GlcNAc 信号传导

• 批准号: 8103267
• 负责人: Steven P Jones
• 金额: $ 36.86万
• 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/8103267
• 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（由申请人提供）：心脏肥大有多种原因（通常是特发性）。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，尽管在心脏中的作用有限。不到 5% 的细胞内葡萄糖被分流至辅助途径，例如己糖胺生物合成途径，它形成称为 O-连接-2-N-乙酰氨基葡萄糖 (O-GlcNAc) 的翻译后修饰的单糖供体。其他实验室已经很好地阐明了与心脏肥大发展相关的许多信号通路，特别是在向衰竭过渡期间。目前的提议将揭示 O-GlcNAc 信号传导对肥厚发展的贡献，此外还了解在压力超负荷引起的心力衰竭中的潜在作用。 PGC-11 被认为是新陈代谢的调节剂，其损失会加重压力超负荷引起的心力衰竭。目前对于肥厚和心力衰竭发展过程中 O-GlcNAc 信号传导与 PGC-11 之间的关系尚不清楚。本研究的目标之一是通过关注 PGC-11 的转录活性来研究 O-GlcNAc 信号传导参与肌细胞对肥大反应的机制。该提案将通过以下方式确定 O-GlcNAc 信号在心肌细胞肥大和心力衰竭发展中的作用： 1) 确定肥厚期间心肌中 O-GlcNAc 信号发生的变化。 2) 确定 O-GlcNAc 信号传导在肥大过程中是否至关重要。 3) 确定肥大期间 O-GlcNAc 信号对 PGC-11 的影响。 4) 阐明肥大期间线粒体水平 O-GlcNAc 信号改变的影响。 PI 的假设是，O-GlcNAc 信号传导在肥大的发展过程中增强，而这种增强是适应不良的。此外，PI 假设 O-GlcNAc 信号传导抑制 PGC-11，并且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了解心肌肥厚发展和心肌衰竭过程中起作用的病理生理机制提供新的见解。公共卫生相关性：确定更有效的心力衰竭治疗方法的一个限制因素是我们对疾病的发生和进展缺乏了解，特别是因为它与代谢信号传导有关。目前的一系列研究将为心脏生长、新陈代谢和压力超负荷引起的肥大的发展机制提供敏锐的见解，这将为创建新疗法奠定基础。