Metabolomics study in patients post myocardial infarction

心肌梗死后患者的代谢组学研究

基本信息

批准号：
9892972
负责人：
Nipavan Chiamvimonvat
金额：
--
依托单位：
VA NORTHERN CALIFORNIA HEALTH CARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892972
关键词：
Acids Acute myocardial infarction Animal Model Animals Anti-Inflammatory Agents Apoptosis Arachidonic Acids Arrhythmia Biological Markers Cancer Center Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cessation of life Chest Clinic Clinical Consent Control Groups Coronary Coupled Cytochrome P450 Data Depressed mood Echocardiography Eicosanoids Enrollment Entomology Enzyme Inhibitor Drugs Enzymes Epoxide hydrolase Evolution Exhibits Fibroblasts Fibrosis Heart Heart Hypertrophy Heart Injuries Heart failure Hospitals Hypertrophy Inflammatory Left Ventricular Ejection Fraction Lipids Long-Term Effects Longitudinal prospective study M-Mode Echocardiography Malignant - descriptor Malignant Neoplasms Medical center Medicine Metabolic Metabolism Microvascular Dysfunction Modeling Morbidity - disease rate Muscle Cells Mutation Myocardial Infarction Myocarditis Oryctolagus cuniculus Outcome Pathway interactions Patients Physicians Play Prevention Property Proteins Recovery Resolution Risk Role Scientist Signal Pathway Stimulus Stress Testing Translating Ventricular Veterans bench to bedside chemokine clinically relevant coronary fibrosis cytokine endoplasmic reticulum stress follow-up high risk improved inhibitor/antagonist insight lipid mediator metabolomics mortality multidisciplinary novel pressure prevent response therapeutic target volunteer

项目摘要

ABSTRACT This proposal represents a bench-to-bedside study to translate our recent findings in small animal models into the clinic. Cardiac remodeling is the heart’s prevailing response to extrinsic and intrinsic stimuli including pressure or volume overload, mutations of sarcomeric proteins, or loss of contractile mass from myocardial infarction (MI). Adverse cardiac remodeling is driven at the cellular level by myocyte hypertrophy, apoptosis, microvascular dysfunction, fibrosis, and electrical perturbations. Our group was the first to demonstrate beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in clinically relevant models of cardiac hypertrophy and failure. SEH is a critical enzyme in the cytochrome P450 pathway. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and myocardial infarction models. Our findings further demonstrate that treatment with sEHIs prevents cardiac fibroblast proliferation and fibrosis. This project is focused on the novel concept that pro-inflammatory metabolites of the cytochrome P450 pathway can result in adverse cardiac remodeling by increasing cardiac myocyte hypertrophy, apoptosis, coupled with a persistent increase in cytokines and chemokines leading to an increase in cardiac fibrosis. Hence, the main objective of this proposal is to use novel metabolomic profiling to determine the mechanistic roles of lipid mediators in adverse cardiac remodeling in patients post MI. New treatment paradigms for adverse cardiac remodeling are likely to be highly impactful.

抽象的该提案代表了一项基准的研究，以翻译我们在小动物模型中的最新发现进入诊所。心脏重塑是心脏对外在和内在刺激的主要反应压力或体积超负荷，肉瘤蛋白的突变或心肌损失梗塞（MI）。心脏肥大，凋亡，凋亡，不良心脏重塑在细胞水平上驱动微血管功能障碍，纤维化和电扰动。我们的小组是第一个展示的新型固体环氧化物水解酶（SEH）抑制剂的有益作用在临床相关模型中心脏肥大和失败。 SEH是细胞色素P450途径中的关键酶。与 SEH抑制剂（SEHIS）可预防心室肌细胞肥大和电重塑压力超负荷和心肌梗塞模型。我们的发现进一步表明了 SEHIS预防心脏成纤维细胞增殖和纤维化。该项目的重点是新颖的概念细胞色素P450途径的促炎性代谢物可以通过增加心肌肥大，凋亡，再加上细胞因子和持续增加趋化因子导致心脏纤维化增加。因此，该提议的主要目的是使用新型代谢组分析，以确定脂质介质的机械作用提前心脏重塑在MI后的患者中。不良心脏重塑的新治疗范例可能会产生很大的影响。