Integrated proteomic and metabolomics analysis of thrombotic myocardial infarction

项目摘要/摘要： 急性心肌梗死(MI)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被广泛认识，并可以 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 血栓，或血液凝块，阻塞血液流动。相比之下，非血栓性心肌梗死继发于 造成氧供需失衡但与动脉粥样硬化无关的机制 斑块破裂或破裂。鉴于心肌细胞死亡是一种常见的病理特征 对于所有的急性心肌梗死，对急性心肌梗死的无创性诊断都是基于对心肌细胞死亡的检测。 目前还不存在区分血栓性和非血栓性心肌梗死的无创性诊断方法 结果是治疗效果不佳，降低了患者的安全性。此外，目前还不清楚这些影响对 血栓性和非血栓性心肌梗死的代谢和生物学过程不同。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鉴别诊断方法 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 给患有急性心肌梗塞的患者。我们将确定血栓形成和血栓形成之间的不同生物过程 非血栓性心肌梗死，这将建议针对潜在原因的治疗干预目标 急性心肌梗塞。在目标1中，我们将利用高分辨率质谱仪来确定绝对浓度 在之前收集的人类受试者的血浆样本中，超过500种蛋白质 已确定病因(血栓性与非血栓性)的急性心肌梗塞。这将使我们能够 确定哪些蛋白质报告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，我们重复了同一个人的测量结果 受试者：陈述时、陈述后6小时，以及稳定的无事件随访时间点3 急性心肌梗塞几个月后。在目标2中，我们将把这一数据与我们现有的关于天然气丰度的数据结合起来 从相同的人体样本中产生的代谢物和脂质。这种集成的数据将有助于 血栓性与非血栓性心肌梗死代谢活动差异的深入分析 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- 独立的系统生物学分析，将突出蛋白质，代谢物和脂类，共同丰富的 并将评估这些相关实体的拓扑结构在血栓形成和非血栓形成之间的不同 血栓性心肌梗塞。在目标3中，我们将开发一个统计分类器，用于确定 急性心肌梗塞。我们将在第二个队列中对该分类器的性能进行盲法评估。

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.