O-GlcNAc Signaling in Heart Failure

描述（由申请人提供）：心脏肥大由多个（通常为特发性）来源引起。压力超负荷诱导心肌细胞肥大，最终可导致心力衰竭。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。葡萄糖代表了代谢的典型底物，尽管在心脏中的程度有限。少于5%的细胞内葡萄糖被分流到辅助途径，例如己糖胺生物合成途径，其形成用于翻译后修饰的单糖供体，称为O-连接的-2-N-乙酰葡糖胺（O-GlcNAc）。许多与心脏肥大的发展有关的信号通路，特别是在向衰竭过渡期间，已经被其他实验室优雅地阐明。本提案将揭示O-GlcNAc信号传导对肥大发展的贡献，以及了解压力超负荷诱导的心力衰竭中的潜在作用。PGC-11被认为是一种代谢调节剂，其缺失可加重压力超负荷诱导的心力衰竭。目前还不知道O-GlcNAc信号和PGC-11之间的关系在肥大和心力衰竭的发展。本研究的一个目的是通过关注PGC-11的转录活性来研究O-GlcNAc信号转导参与心肌细胞对肥大的反应的机制。该提议将通过以下方式鉴定O-GlcNAc信号传导在心肌细胞肥大和心力衰竭的发展中的作用：1）确定在肥大期间心肌中O-GlcNAc信号传导发生什么变化。2)确定O-GlcNAc信号传导在肥大期间是否是必需的。3)鉴定肥大期间O-GlcNAc信号传导对PGC-11的影响。4)阐明在肥大期间改变的O-GlcNAc信号传导在线粒体水平上的影响。PI的假设是O-GlcNAc信号传导在肥大发展期间增强，并且这种增强是适应不良的。此外，PI假定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。从这样的机制研究的结果将提供新的见解的病理生理机制的发展过程中的肥大和失败的心肌。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有关。目前的一系列研究将为心脏生长、代谢和压力超负荷诱导的肥大的发展机制提供敏锐的见解，这将为创造新的治疗方法奠定基础。

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.