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）是美国最常见的慢性心脏病类型，也是充血性心力衰竭的常见潜在病因。尽管如此，ICM 的潜在分子机制仍不清楚。此外，如果不及时治疗，慢性 ICM 的预后非常差。因此，更好地了解疾病机制并确定特异性生物标志物对于 ICM 的早期检测和治疗非常重要。肌节中的肌丝蛋白不仅在心肌收缩力中发挥重要作用，而且是心肌收缩力的关键元素。 心力衰竭发作和进展期间的信号接收和转导。该假设认为，心肌梗死后 (MI) 适应不良的心脏重塑可能导致肌丝中与心脏功能障碍相关的蛋白质修饰发生改变，并提供 ICM 的潜在诊断和预后生物标志物。尽管多种肌丝翻译后修饰（PTM）被认为在调节心脏功能中协同作用，但 缺乏同时对肌丝蛋白进行全面分析并评估与心脏功能相关的所有协同 PTM 变化。在此，我们将采用创新的集成“自上而下”蛋白质质谱（MS）为基础的疾病蛋白质组学平台，同时检查从健康和患病猪和人类心肌中提取的肌丝蛋白，并识别肌丝修饰中所有与疾病相关的变化。目标 1 将鉴定 MI 后 ICM 模型患病猪心肌肌丝中蛋白质修饰的改变，并确定其功能后果。目标 2 将确定 ICM 患者终末期衰竭人类心肌中肌丝的改变及其功能后果。目标 3 将评估新型肌丝修饰对 Ca2+ 介导的心肌收缩和舒张的功能影响。将与蛋白质组学实验同时测量带皮心肌制剂的机械特性（等长力和力的 Ca2+ 敏感性）。此外，我们将评估区域收缩和舒张功能，以建立特定蛋白质组变化与体内和离体心脏功能之间的机制联系。随着该项目的完成，我们期望识别肌丝中多种功能上显着的改变，并了解这些改变如何协同作用，在心肌梗死后左心室重构至衰竭期间调节适应不良信号。我们研究的成功将为 ICM 的潜在机制提供新的见解，并将确定新的候选生物标志物，用于早期检测 ICM 的存在和进展。