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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：
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
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/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

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.

项目概要/摘要：急性心肌梗死（MI）是指心肌缺血，心脏供血不足肌肉，随后是心肌细胞死亡。急性心肌梗死的多种原因已被广泛认识并可能分类为血栓性、非血栓性和继发于冠状动脉手术的急性MI。机械论血栓性MI的原因是动脉粥样硬化斑块的破裂或侵蚀，导致血栓形成。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裂。鉴于心肌细胞死亡是常见的病理特征对于所有急性MI，急性MI的非侵入性诊断是基于心肌细胞死亡的检测。目前不存在用于区分血栓性MI和非血栓性MI的非侵入性诊断，导致治疗效果不佳并降低患者安全。此外，尚不清楚对血栓性和非血栓性MI之间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。我们将开发一种诊断方法，用于非侵入性鉴别血栓性MI与非血栓性MI的比较，这将使治疗药物能够更早、更安全和更精确地靶向急性心肌梗死患者的治疗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MI，这将提示针对潜在原因的治疗干预靶点急性心肌梗塞。在目标1中，我们将利用高分辨率质谱法确定绝对浓度在先前从经历过一种疾病的人类受试者收集的血浆样品中，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急性心肌梗死的原因，而不是心肌细胞的存在死亡我们的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小时和稳定无事件随访时间点3 在急性心肌梗死后几个月。在目标2中，我们将把这些数据与我们现有的关于代谢物和脂质产生自相同的人类受试者样品。这一综合数据将有助于深入分析血栓性和非血栓性MI之间代谢酶活性的差异，途径、受体-配体结合事件和其他生化反应。进一步我们将进行数据处理- 依赖系统生物学分析，将突出蛋白质，代谢物和脂质，共同丰富的，血浆并将评估这些相关实体的拓扑结构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，用于确定急性心肌梗死我们将在第二个队列中对该分类器的性能进行盲法评估。