MPO, HDL Dysfunction and Cardiovascular Disease

MPO、HDL 功能障碍与心血管疾病

• 批准号: 8987161
• 负责人: YUQING Eugene CHEN
• 金额: $ 71.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987161
• 关键词: Adverse effects; Affect; Angiography; Animal Model; Animals; Antiatherogenic; Apolipoprotein A-I; Arterial Fatty Streak; Atherosclerosis; Biological Markers; Biology; Cardiac Catheterization Procedures; Cardiovascular Diseases; Characteristics; Cholesterol; Clustered Regularly Interspaced Short Palindromic Repeats; Coronary; Coronary heart disease; Data; Development; Diagnostic; Diet; Disease; Drug Targeting; Endothelium; Enzymes; Event; Failure; Framingham Heart Study; Functional disorder; High Density Lipoproteins; Human; Individual; Inflammatory; Knock-out; Knowledge; Lipids; Low-Density Lipoproteins; Mediator of activation protein; Modeling; Molecular; Monitor; Mus; Myocardial Infarction; Myocardial dysfunction; Nicotinic Acids; Oryctolagus cuniculus; Oxidative Stress; Pathogenesis; Patients; Peroxidases; Pharmaceutical Preparations; Plague; Proteomics; Reporting; Role; Rupture; Source; Sudden Death; Technology; Therapeutic; Time; Tissues; Work; atherogenesis; atheroprotective; base; clinically relevant; enzyme activity; epidemiology study; heme a; inhibitor/antagonist; macrophage; novel; oxidation; particle; protein expression; public health relevance; research and development; research study; tool; torcetrapib

 DESCRIPTION (provided by applicant): Oxidative stress is implicated in atherogenesis and plaque rupture-the major cause of myocardial infarction (MI) and sudden death. One of the well-characterized sources of oxidative stress is myeloperoxidase (MPO), a heme enzyme that co-localizes with macrophages in human atherosclerotic lesions. Epidemiology studies show that individuals possessing high MPO levels among sequential subjects undergoing diagnostic cardiac catheterization were 15- to 20-fold more likely to demonstrate abnormal coronary angiograms compared with subjects in the lowest quartile. Consistently, individuals with total or subtotal MPO deficiency appear less likely to have CVD development. Importantly, MPO selectively modifies apolipoprotein A-1 (ApoA-I), generating dysfunctional HDL. Here we hypothesize that inhibiting MPO is beneficial to the quality of HDL, which consequently exert atheroprotective effects on the patients. We propose experiments to determine whether MPO is an effective target for reducing atherosclerosis, and to define the roles of MPO on HDL functionality in atherogenesis. We have successfully generated MPO knockout (KO) rabbits using the CRISPR/Cas9 technology. These novel rabbit models will be employed in the present study. We expect establishing a meaningful animal model for the study of MPO biology, gaining novel knowledge, and facilitating the R&D of MPO based therapeutics and diagnostics. Specifically, we will 1) Determine whether MPO is an effective target for reducing atherosclerosis in rabbits; 2) Define the roles of MPO on HDL functionality in atherogenesis using novel rabbit models. It is well documented that mice are not appropriate for the study of MPO biology. Only trace amount of MPO can be detected in atherosclerotic tissues in mice, dwarf to that found in human counterpart. Moreover, mice deficient of MPO showed increased atherosclerosis, opposite to what is observed in humans. This project thus has a unique advantage in resolving such debate (i.e. MPO be atherogenic or anti-atherogenic) by using the novel MPO knockout rabbit models, a species that has been a classic model to study human lipid biology and CVD.

 描述（由适用提供）：氧化应激隐含在动脉粥样硬化和斑块破裂中 - 心肌梗塞（MI）和猝死的主要原因。氧化应激的特征来源之一是髓过氧化物酶（MPO），这是一种血红素酶，它与人动脉粥样硬化病变中的巨噬细胞共定位。流行病学研究表明，与最低四分位数中的受试者相比，接受诊断性心脏导管插入术的顺序受试者中具有高MPO水平的个体可能表现出异常的冠状动脉血管造影。始终如一，具有总MPO缺乏外观的个体具有CVD发展的可能性较小。重要的是，MPO选择性修饰载脂蛋白A-1（APOA-I），从而产生功能失调的HDL。在这里，我们假设抑制MPO对HDL的质量有益，从而对患者产生动脉保护作用。我们提出了实验，以确定MPO是否是减少动脉粥样硬化的有效靶标，并定义MPO在HDL功能在动脉粥样硬化中的作用。我们使用CRISPR/CAS9技术成功地生成了MPO敲除（KO）兔子。这些新型的兔子模型将在本研究中聘请。我们希望建立一个有意义的动物模型，用于研究MPO生物学，获得新颖的知识以及支持基于MPO的理论和诊断的R＆D。具体而言，我们将1）确定MPO是否是减少兔子动脉粥样硬化的有效靶标； 2）使用新型兔模型定义了MPO在动脉粥样硬化中的HDL功能上的作用。有充分的文献证明，小鼠不适合研究MPO生物学。在小鼠的动脉粥样硬化组织中，只能检测到痕量的MPO，矮至在人类对应物中发现的小鼠。此外，缺乏MPO的小鼠表现出增加的动脉粥样硬化，与人类观察到的相反。因此，通过使用新型的MPO基因敲除兔模型，该项目在解决此类辩论（即MPO是动脉粥样硬化或抗动脉粥样硬化）方面具有独特的优势，该物种一直是研究人脂质生物学和CVD的经典模型。