Project 5 - Metabolomic Analysis of Atherothrombosis

项目 5 - 动脉粥样硬化血栓形成的代谢组学分析

• 批准号: 8891457
• 负责人: Andrew DeFilippis
• 金额: $ 27.4万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891457
• 关键词: Biological Markers; Cardiovascular Diseases; Cause of Death; Clinical Management; Coronary; Coronary Thrombosis; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic tests; Effectiveness; Event; Goals; Individual; Intervention; Lead; Lesion; Measurement; Measures; Myocardial; Myocardial Ischemia; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Production; Research; Safety; Thrombus; Treatment Protocols; accurate diagnosis; acute coronary syndrome; atherothrombosis; cardiovascular disorder risk; cohort; diagnostic accuracy; improved; metabolomics; mortality; myocardial damage; oxidized lipid; young adult

Cardiovascular disease (CVD) is the leading cause of death in individuals with diabetes with rates of acute coronary syndrome (ACS) and total mortality several fold higher in younger adults with versus without type 2 diabetes (T2D). Nevertheless, the mechanisms that impart greater CVD risk in T2D are not well understood and no diabetes-specific CVD treatment regimens have been developed. ACS occurs when intracoronary thrombus obstructs coronary flow to produce myocardial ischemia and is responsible for the majority of irreversible myocardial damage in T2D. Although great advances have been made in diagnosing ACS, all of the current ACS biomarkers measure the result, myocardial necrosis, and not the cause and therapeufic target -atherothrombosis. The ability to identify atherothrombotic-MI at the start of the event, prior to irreversible myocardial necrosis, and quickly disfinguish atherothrombotic from non-atherothrombofic ACS would materially increase the safety and effectiveness of ACS treatment in T2D patients. The long-term goal of this project is to develop a biomarker which differentiates atherothrombotic from non-atherothrombotic Ml in patients with T2D. Such an approach will not only improve diagnostic accuracy but could also potentially identify events at the start of coronary thrombosis, prior to "inevitable" myocardial necrosis, allowing for more prompt and targeted interventions. Hence, using both targeted and unbiased metabolomic approaches, we plan to identify specific biomarkers of atherothrombosis. Our central hypothesis is atherothrombotic events are associated with increased production of metabolites derived from oxidized lipids in the culprit lesion or generated by the atherothrombotic event itself and that measurement of these metabolites will allow for eariy and accurate diagnosis of atherothrombotic Ml is T2D patients.

心血管疾病（CVD）是糖尿病患者死亡的主要原因， 冠状动脉综合征（ACS）和总死亡率在年轻成人与非2型高出几倍 糖尿病（T2 D）。然而，T2 D中赋予更大CVD风险的机制尚不清楚 并且还没有开发出糖尿病特异性CVD治疗方案。当冠状动脉内 血栓阻塞冠状动脉血流，造成心肌缺血， 2型糖尿病不可逆性心肌损伤。虽然在诊断ACS方面取得了很大进展，但所有 目前的ACS生物标志物测量结果，心肌坏死，而不是原因和治疗。 目标-动脉粥样硬化血栓形成。在事件开始时，在 不可逆性心肌坏死，并快速区分动脉粥样硬化血栓形成性和非动脉粥样硬化血栓形成性ACS 将显著增加T2 D患者ACS治疗的安全性和有效性。远景目标 该项目的目的是开发一种区分动脉粥样硬化血栓形成与非动脉粥样硬化血栓形成的Ml的生物标志物 在T2 D患者中。这种方法不仅可以提高诊断的准确性， 在“不可避免的”心肌坏死之前，在冠状动脉血栓形成开始时识别事件， 及时和有针对性的干预。因此，使用靶向和无偏代谢组学方法，我们 计划确定动脉粥样硬化血栓形成的特定生物标志物。我们的中心假设是动脉粥样硬化血栓形成事件 与来源于罪犯病变中氧化脂质的代谢产物的产生增加有关，或 这些代谢物的测量将允许早期检测动脉粥样硬化血栓形成事件本身产生的代谢物， 动脉粥样硬化血栓性M1的准确诊断是T2 D患者。