Deciphering Myofilament Modifications in Ischemic Cardiomyopathy

破译缺血性心肌病中的肌丝修饰

• 批准号: 8605545
• 负责人: Ying Ge
• 金额: $ 36.87万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605545
• 关键词: Address; Biological Markers; Cardiac; Cardiac Muscle Contraction; Cardiomyopathies; Chronic; Clinical; Complement; Congestive Heart Failure; Contractile Proteins; Country; Detection; Development; Diagnostic; Disease; Disease Progression; Early Diagnosis; Early treatment; Epidemic; Etiology; Failure; Family suidae; Functional disorder; Heart; Heart Diseases; Heart failure; Human; Indium; Isometric Exercise; Knowledge; Left; Left Ventricular Remodeling; Link; Mass Spectrum Analysis; Measures; Mechanics; Mediating; Microfilaments; Modeling; Modification; Molecular; Monitor; Morbidity - disease rate; Muscle Cells; Muscle relaxation phase; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Outcome; Patients; Phosphorylation; Play; Post-Translational Protein Processing; Preparation; Prognostic Marker; Property; Protein Isoforms; Proteins; Proteomics; RNA Splicing; Recombinants; Regulation; Relaxation; Reproducibility; Research; Role; Sampling; Sarcomeres; Signal Transduction; Site; Skin; Staging; Technology; United States; Variant; Ventricular; acute coronary syndrome; base; clinically relevant; improved; in vivo; innovation; insight; mortality; mutant; new therapeutic target; novel; outcome forecast; protein expression; public health relevance; research study; stoichiometry; success; tandem mass spectrometry; tool

DESCRIPTION (provided by applicant): Ischemic cardiomyopathy (ICM) is the most prevalent type of chronic heart diseases in the United States and a common underlying etiology of congestive heart failure. Nonetheless the underlying molecular mechanism of ICM remains unclear. Moreover, the prognosis of chronic ICM is very poor if left untreated. Therefore it is highly important to gain a better understanding of the disease mechanism and to identify specific biomarkers for early detection and treatment of ICM. Myofilament proteins in the sarcomeres not only play essential roles in cardiac contractility but also are critical elements in signal reception and transduction during the onset and progression to heart failure. The hypothesis is that post-myocardial infarction (MI) maladaptive cardiac remodeling can result in altered protein modifications in myofilaments that are associated with cardiac dysfunction and offer potential diagnostic and prognostic biomarkers of ICM. Although multiple myofilament post-translational modifications (PTMs) are believed to act in concert in regulating cardiac function, a comprehensive analysis of myofilament proteins simultaneously and assess all synergistic PTM changes related to cardiac function is lacking. Herein, we will employ an innovative integrated "top-down" protein mass spectrometry (MS)-based disease proteomics platform to simultaneously examine myofilament proteins extracted from healthy and diseased swine and human myocardium and identify all disease-related changes in myofilament modifications. Aim 1 will identify altered protein modifications in myofilaments from diseased swine myocardium of post-MI ICM model and determine their functional consequences. Aim 2 will determine myofilament alterations in end-stage failing human myocardium from ICM patients and their functional consequences. Aim 3 will assess the functional effects of novel myofilament modifications in Ca2+-mediated cardiac muscle contraction and relaxation. Mechanical properties (the isometric force and the Ca2+-sensitivity of the force) will be measured in skinned myocardial preparations in parallel to proteomics experiments. Furthermore, we will assess regional systolic and diastolic function to establish mechanistic links between specific proteomic changes and in vivo and ex vivo cardiac function. With the completion of this project, we expect to identify multiple functionally significant alterations in myofilaments and understand how these alterations act in concert to modulate maladaptive signaling during post-MI left ventricular remodeling to failure. The success of our research will provide new insights into the mechanisms underlying ICM and will identify new candidate biomarkers for early detection of the presence and progression of ICM.

描述（由申请人提供）：缺血性心肌病（ICM）是美国最普遍的慢性心脏病类型，也是充血性心力衰竭的常见潜在病因。尽管如此，ICM的基本分子机制仍不清楚。此外，如果未经治疗，慢性ICM的预后非常差。因此，更好地了解疾病机制并确定特定的生物标志物以早期检测和治疗ICM非常重要。肉瘤中的肌丝蛋白不仅在心脏收缩性中起重要作用，而且是关键元素 信号接收和发作过程中的转导，并发展为心力衰竭。假设是，心肌后梗死（MI）不良心脏的心脏重塑可能会导致与心脏功能障碍相关的肌膜的蛋白质修饰改变，并提供ICM的潜在诊断和预后的生物：ICM的潜在诊断和预后。尽管据信多种翻译后修饰（PTM）在调节心脏功能方面起作用，但 缺乏同时对肌丝蛋白的全面分析，并评估所有与心脏功能有关的协同PTM变化。本文中，我们将采用创新的综合“自上而下”蛋白质质谱法（MS）疾病蛋白质组学平台，同时检查从健康和患病的猪和人体心肌中提取的肌丝蛋白，并确定所有与疾病相关的肌膜修饰变化。 AIM 1将鉴定出MI ICM模型患病猪心肌的肌膜中蛋白质修饰的改变，并确定其功能后果。 AIM 2将确定ICM患者末期失败的人体心肌及其功能后果的骨膜改变。 AIM 3将评估在Ca2+介导的心肌收缩和放松中新型肌丝修饰的功能效应。机械性能（力量和力的Ca2+ - 敏感性）将在与蛋白质组学实验并行的皮肤心肌制剂中测量。此外，我们将评估区域收缩和舒张功能，以在特定的蛋白质组学变化与体内和离体心脏功能之间建立机械联系。随着该项目的完成，我们期望确定肌丝的多个功能上重大的变化，并了解这些变化在MI后左心室重塑期间如何协同调节适应不良的信号传导。我们研究的成功将为ICM基础机制提供新的见解，并将确定新的候选生物标志物，以尽早发现ICM的存在和进展。