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

• 批准号: 10553215
• 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
• 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/10553215
• 关键词: Acute myocardial infarction; Address; Affect; Angiography; Arterial Fatty Streak; Biochemical Reaction; Biological; Biological Markers; Biological Process; Blinded; Blood coagulation; Blood flow; Cardiac Myocytes; Categories; 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; Patient-Focused Outcomes; 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; cohort; data integration; 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; patient safety; proteomic signature; receptor; statistical and machine learning; targeted treatment; thrombotic; treatment strategy

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 造成氧供需不平衡的机制，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 之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 MI。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体内共同丰富的蛋白质、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。