Deciphering Myofilament Modifications in Ischemic Cardiomyopathy

项目总结/摘要 心肌梗死（MI）是心力衰竭（HF）最常见的原因，但其分子机制 MI后心肌中潜在的心功能不全仍不清楚。此外，目前的HF治疗 主要集中在适应不良心室重构发生后的症状管理。但 全面了解早期（适应性）重塑的分子变化有助于 开发治疗以预防晚期（适应不良）重塑和HF。心室重构是 其特征在于肌节的改变，肌节由两侧为Z盘的肌丝组成。邮报- 肌节蛋白的翻译修饰（PTM）调节收缩性。此外，心肌收缩力 高度依赖于ATP的生成，因此ATP生成过程中的损伤可迅速导致 收缩功能障碍已知缺血的发作与心脏组织的显著改变有关， 新陈代谢.代谢酶的PTM在调节代谢途径中起着关键作用。所以我们 假设肌节和代谢蛋白修饰协同失调有助于 心肌梗死后早期心室重构时的收缩功能障碍。为了验证我们的假设，我们将使用 一种新的系统生物学方法，通过整合自上而下的蛋白质组学和代谢组学的多组学实现 通过体内和离体功能研究来描述MI后早期的分子机制 心室重构这种新的多组学方法可以准确评估蛋白质组的变化 和代谢组，以了解肌节的协调失调， 以及代谢性PTM和代谢物。此外，我们将使用大动物（猪）MI模型的组合 和临床缺血性心肌病（ICM）组织，以加速我们的发现，以帮助诊断 和人类的治疗干预。目的1将确定肌丝和Z盘的协调变化 心肌梗死后猪心肌中的蛋白质，并与两种性别的收缩功能障碍有关。目标2将决定 心肌梗死后心肌重构中蛋白质组和代谢组的改变。目标3将确定 ICM患者心肌中的肌节和代谢标志物，并评估其在ICM患者中的功能后果。 考虑合并症和性别差异。这种跨学科和翻译/临床应用 具有很强的科学前提和直接临床相关性的新假设。它 将提供一项全面的研究，以全面表征代谢和肌节中的各种PTM 蛋白质以及心脏代谢和收缩功能障碍之间的失调之间的相互作用。 它具有直接的翻译潜力，导致深入了解的基础机制，在 早期心肌梗死后重塑和新的肌节和代谢特征的发现， 早期诊断ICM的标志物。

Project Summary/Abstract Myocardial infarction (MI) is the most common cause of heart failure (HF), but the molecular mechanisms underlying cardiac dysfunction in the post-MI myocardium remain unclear. Moreover, current treatments for HF mainly focus on symptom management after maladaptive ventricular remodeling has occurred. However, a comprehensive understanding of molecular changes at the early-phase (adaptive) remodeling could aid in the development of treatments to prevent late-phase (maladaptive) remodeling and HF. Ventricular remodeling is characterized by alterations in the sarcomere composed of myofilaments flanked by Z-discs. The post- translational modifications (PTMs) of the sarcomeric proteins regulate contractility. Moreover, cardiac contractility highly depends on ATP generation and thus impairment in the ATP-generating processes can rapidly lead to contractile dysfunction. The onset of ischemia is known to be associated with dramatic alterations in cardiac metabolism. PTMs of metabolic enzymes play a key role in regulating the metabolic pathways. Therefore, we hypothesize that concerted dysregulations of sarcomeric and metabolic protein modifications contribute to contractile dysfunction at the early-phase post-MI ventricular remodeling. To test our hypothesis, we will employ a novel systems biology approach enabled by multi-omics integrating top-down proteomics and metabolomics with in vivo and ex vivo functional studies to delineate the molecular mechanism underlying early-phase post-MI ventricular remodeling. This novel multi-omics method allows accurate assessment of changes in the proteome and metabolome from the same heart tissue sample to understand the concerted dysregulation of sarcomeric and metabolic PTMs and metabolites. Moreover, we will use a combination of a large animal (swine) MI model and clinical ischemic cardiomyopathy (ICM) tissues to accelerate translation of our findings to aid in diagnostic and therapeutic interventions in humans. Aim 1 will identify concerted changes in the myofilament and Z-disc proteins in post-MI swine myocardium and relate to contractile dysfunction in both sexes. Aim 2 will determine the metabolic alterations in both proteome and metabolome in the post-MI remodeling. Aim 3 will identify sarcomeric and metabolic markers in ICM patient myocardium and assess their functional consequences in consideration of comorbidities and sex differences. This interdisciplinary and translational/clinical application is highly significant with a strong scientific premise and a novel hypothesis of direct clinical relevance. It will provide a comprehensive study to globally characterize a variety of PTMs in metabolic and sarcomeric proteins as well as the interplay between dysregulation between cardiac metabolism and contractile dysfunction. It has direct translational potential leading to an in-depth understanding of the underlying mechanisms at the early-phase post-MI remodeling and discovery of new sarcomeric and metabolic signatures as a panel of markers for diagnosis of ICM at early-stage.