MPO, HDL Dysfunction and Cardiovascular Disease

MPO、HDL 功能障碍与心血管疾病

基本信息

批准号：
9265931
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
项目类别：
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/9265931
关键词：
Adverse effects Affect Angiography Animal Model Animal Testing Alternatives Animals Antiatherogenic Apolipoprotein A-I Arterial Fatty Streak Atherosclerosis Biological Markers Biology CRISPR/Cas technology Cardiac Catheterization Procedures Cardiovascular Diseases Characteristics Cholesterol Coronary Coronary heart disease Data Development Diagnostic Diet Disease Drug Targeting 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 Oxides Pathogenesis Patients Peroxidases Pharmaceutical Preparations Pharmacology Proteins Proteomics Reporting Role Rupture Source Study models Sudden Death Technology Therapeutic Time Tissues Work atherogenesis atheroprotective base biomarker panel clinically relevant diagnostic panel enzyme activity epidemiology study experimental study heme a inhibitor/antagonist macrophage novel oxidation particle public health relevance research and development tool torcetrapib

项目摘要

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（由申请人提供）：氧化应激与动脉粥样硬化和斑块破裂有关，这是心肌梗死（MI）和猝死的主要原因之一，氧化应激的一个明确来源是髓过氧化物酶（MPO），它是一种血红素酶，可导致心肌梗死（MI）和猝死。流行病学研究表明，在接受心脏诊断的连续受试者中，MPO 水平较高。与最低四分位数的受试者相比，导管插入术显示异常冠状动脉血管造影的可能性高出 15 至 20 倍。同样，MPO 完全或部分缺乏的个体似乎不太可能发生 CVD。重要的是，MPO 选择性地改变载脂蛋白 A-1。 ApoA-I），产生功能失调的 HDL。在这里，我们追求抑制 MPO 有利于 HDL 的质量，从而对患者产生动脉粥样硬化作用。确定 MPO 是否是减少动脉粥样硬化的有效靶点，并确定 MPO 在动脉粥样硬化形成中对 HDL 功能的作用，我们已使用 CRISPR/Cas9 技术成功生成了 MPO 敲除 (KO) 兔子，这些新型兔子模型将用于研究。我们期望建立一个有意义的动物模型来研究 MPO 生物学，获得新的知识，并促进基于 MPO 的治疗和诊断的研发。具体来说，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) 使用新型兔子模型确定 MPO 对 HDL 功能的作用，有充分证据表明小鼠不适合研究 MPO 生物学，只能检测到痕量的 MPO。此外，缺乏 MPO 的小鼠表现出动脉粥样硬化增加，这与在人类中观察到的情况相反，因此该项目在解决这一问题方面具有独特的优势。通过使用新型 MPO 敲除兔模型（该物种已成为研究人类脂质生物学和 CVD 的经典模型），可以解决此类争论（即 MPO 是致动脉粥样硬化还是抗动脉粥样硬化）。