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）：心脏肥大来自多种，通常是特发性，起源。压力超负荷会诱导心肌细胞肥大，最终会导致心力衰竭。病理肥大的诱导涉及代谢机制的转录重编程。因此，肥大涉及代谢障碍，导致心脏功能障碍。葡萄糖代表代谢的典型底物，尽管在心脏中有限。不到5％的细胞内葡萄糖被分解为辅助途径，例如己糖胺生物合成途径，该途径形成了用于翻译后修饰的单糖供体，称为O-linked-2-N-乙酰葡萄糖（O-GLCNAC）。与心脏肥大发展有关的许多信号通路，尤其是在失败过渡期间，已被其他实验室优雅地阐明。本建议还将揭示O-GLCNAC信号对肥大发展的贡献，除了了解压力超负荷引起的心力衰竭中的潜在作用。 PGC-11被认为是代谢的调节剂，其损失会加剧压力超负荷引起的心力衰竭。目前，在肥大和心力衰竭发展过程中O-GLCNAC信号传导与PGC-11之间的关系尚无。本研究的一个目标是研究O-GLCNAC信号传导通过关注PGC-11的转录活性来参与心肌细胞对肥大的反应的机制。该建议将通过以下方式确定O-GLCNAC信号在心肌肥大和心力衰竭发展中的作用：1）确定肥大过程中心肌中O-GLCNAC信号传导发生了什么变化。 2）确定在肥大期间O-GLCNAC信号是否必不可少。 3）确定肥大过程中O-GLCNAC信号对PGC-11的影响。 4）阐明在肥大期间线粒体水平上O-GlCNAC信号改变的影响。 PI的假设是在肥大发展过程中O-GLCNAC信号被增强，并且这种增强是适应不良的。此外，PI认为O-GLCNAC信号传导抑制了PGC-11，并且此类变化对肥厚和失败表型的发展具有重要作用。此类机械研究的发现将提供对肥大发展和心肌失败过程中病理生理机制的新见解。公共卫生相关性：确定心力衰竭更有效治疗方法的一个限制因素是我们对疾病的起始和进展缺乏了解，尤其是与代谢信号传导有关的问题。本系列研究将为心脏生长，代谢机制以及压力超负荷引起的肥大的发展提供敏锐的见解，这将为创造新的治疗剂的创造奠定基础。