Integrated proteomic and metabolomics analysis of thrombotic myocardial infarction

血栓性心肌梗死的蛋白质组学和代谢组学综合分析

基本信息

批准号：
10337207
负责人：
Patrick J Trainor
金额：
$ 22.2万
依托单位：
NEW MEXICO STATE UNIVERSITY LAS CRUCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10337207
关键词：
Acute myocardial infarction Address Affect Arterial Fatty Streak Biochemical Reaction Biological Biological Markers Biological Process Blinded Blood coagulation Blood flow Cardiac Myocytes Cause of Death Cell Death Cell-Cell Adhesion Cessation of life Characteristics Classification Clinical Coagulation Process Coronary Coronary Arteriosclerosis Data Detection Development Diagnostic Diagnostic Procedure Diagnostic tests Ensure Etiology Evaluation Event Fibrinolysis Guidelines Hour Human Infarction International Investigation Knowledge Ligand Binding Ligands Lipids Mass Spectrum Analysis Measures Metabolic Metabolic Pathway Metabolism Methods Modeling Monitor Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Necrosis Oxygen Pathologic Patients Performance Plasma Plasma Proteins Platelet Activation Procedures Process Proteins Proteome Proteomics Reaction Reporting Research Design Resolution Rupture Sampling Secondary to Statistical Models System Systems Biology Therapeutic Intervention Thrombosis Thrombus Time United States Vascular blood supply Work atherosclerotic plaque rupture base cohort design diagnostic criteria differential expression experience feature selection follow-up genome-wide human subject improved insight lipid metabolism lipidomics liquid chromatography mass spectrometry metabolome metabolomics mortality multiple omics new therapeutic target noninvasive diagnosis novel diagnostics optimal treatments patient safety protein metabolite proteomic signature receptor safety outcomes statistical and machine learning targeted treatment thrombotic treatment strategy

项目摘要

Project Summary / Abstract: Acute myocardial infarction (MI) is defined as myocardial ischemia, the inadequate supply of blood to heart muscle, followed by myocardial cell death. Multiple causes of acute MI are widely recognized and can be categorized as thrombotic, non-thrombotic, and acute MI secondary to coronary procedures. The mechanistic cause of a thrombotic MI is the rupture or erosion of an atherosclerotic plaque that results in the formation of a thrombus, or blood clot, which occludes the flow of blood. In contrast, non-thrombotic MI occurs secondary to mechanisms which create an oxygen supply and demand imbalance, but are not associated with atherosclerotic plaque rupture or disruption. Given that myocardial cell death is the pathological characteristic that is common to all acute MI, non-invasive diagnostics for acute MI are based on the detection of myocardial cell death. Currently non-invasive diagnostics for differentiating thrombotic MI from non-thrombotic MI do not exist which results in sub-optimal treatment and diminished patient safety. Further, it is not known how the impacts on metabolism and biological processes differ between thrombotic and non-thrombotic MI. In this project, we will address both of these problems. We will develop a diagnostic method for the non-invasive differentiation of thrombotic MI versus non-thrombotic MI that will enable earlier, safer, and more precise targeting of therapeutics to patients suffering from acute MI. We will determine biological processes that differ between thrombotic and non-thrombotic MI, which will suggest targets for therapeutic intervention that are specific to the underlying cause of an acute MI. In Aim 1 we will utilize high resolution mass spectrometry to determine the absolute concentration of over 500 proteins in previously collected plasma samples from human subjects who were experiencing an acute MI for which the cause (thrombotic versus non-thrombotic) was determined. This will enable us to determine which proteins report on the cause of the acute MI as opposed to the presence of myocardial cell death. A critical advantage of our study design is that we have repeated measures from the same human subjects: at the time of presentation, 6 hours post-presentation, and at a stable event-free follow-up timepoint 3 months after the acute MI. In Aim 2 we will integrate this data with our existing data on the abundances of metabolites and lipids generated from the same human subject samples. This integrated data will facilitate an in-depth analysis of the differences between thrombotic and non-thrombotic MI in the activities of metabolic pathways, receptor-ligand binding events, and other biochemical reactions. Further we will conduct data- dependent systems biology analyses that will highlight proteins, metabolites, and lipids that are co-abundant in plasma and will evaluate how the topology of these related entities differs between thrombotic and non- thrombotic MI. In Aim 3 we will develop a statistical classifier for the determination of the underlying cause of an acute MI. We will conduct a blinded evaluation of the performance of this classifier in a second cohort.

项目摘要/摘要：急性心肌梗塞（MI）被定义为心肌缺血，即心脏供血不足肌肉，然后是心肌细胞死亡。急性心肌梗死的多种原因已得到广泛认可，并且可以分为血栓性、非血栓性和继发于冠状动脉手术的急性心肌梗死。机械论血栓性心肌梗死的原因是动脉粥样硬化斑块的破裂或侵蚀，导致形成血栓或血凝块，阻塞血液流动。相反，非血栓性 MI 继发于造成氧供需失衡的机制，但与动脉粥样硬化无关斑块破裂或破坏。鉴于心肌细胞死亡是常见的病理特征对于所有急性心肌梗死，急性心肌梗死的无创诊断都是基于心肌细胞死亡的检测。目前尚不存在用于区分血栓性 MI 和非血栓性 MI 的非侵入性诊断方法。导致治疗效果不佳并降低患者安全。此外，尚不清楚这会如何影响血栓性心肌梗死和非血栓性心肌梗死的代谢和生物过程有所不同。在这个项目中，我们将解决这两个问题。我们将开发一种非侵入性分化的诊断方法血栓性心肌梗死与非血栓性心肌梗死相比，可以更早、更安全、更精确地靶向治疗患有急性心肌梗死的患者。我们将确定血栓形成和血栓形成之间不同的生物过程非血栓性心肌梗死，这将建议针对根本原因的治疗干预目标急性心肌梗死。在目标 1 中，我们将利用高分辨率质谱法来确定绝对浓度先前从正在经历疾病的人类受试者中采集的血浆样本中含有超过 500 种蛋白质已确定原因（血栓性与非血栓性）的急性心肌梗死。这将使我们能够确定哪些蛋白质报告了急性心肌梗死的原因，而不是心肌细胞的存在死亡。我们研究设计的一个关键优势是我们对同一个人进行了重复测量受试者：就诊时、就诊后 6 小时以及稳定的无事件随访时间点 3 急性心肌梗死发生后几个月。在目标 2 中，我们将把这些数据与现有的丰度数据整合起来。从相同的人类受试者样本中产生的代谢物和脂质。这些综合数据将有助于深入分析血栓性和非血栓性心肌梗死代谢活动的差异途径、受体-配体结合事件和其他生化反应。此外，我们将进行数据- 依赖性系统生物学分析将突出显示在细胞中共同丰富的蛋白质、代谢物和脂质血浆并将评估这些相关实体的拓扑在血栓性和非血栓性之间有何不同血栓性心肌梗死。在目标 3 中，我们将开发一个统计分类器，用于确定问题的根本原因。急性心肌梗死。我们将在第二组中对该分类器的性能进行盲法评估。