Myeloperoxidase, Chronic Kidney Disease and Atherosclerosis

髓过氧化物酶、慢性肾脏病和动脉粥样硬化

• 批准号: 9761571
• 负责人: Anna Vachaparampil Mathew
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761571
• 关键词: 3-nitrotyrosine; Activities of Daily Living; Address; Adult; Affect; Amino Acids; Animal Model; Animals; Arterial Fatty Streak; Atherosclerosis; Biology; Blood Vessels; Bone Marrow Transplantation; Cardiovascular system; Cause of Death; Characteristics; Cholesterol; Chronic Kidney Failure; Clinical Research; Coronary Arteriosclerosis; Coupled; Cross-Sectional Studies; Diagnostic; Diagnostic tests; Dialysis procedure; Disease Progression; Engineering; Enzymes; Event; Exposure to; General Population; Glomerular Filtration Rate; Goals; Heart Diseases; Heart Rate; High Density Lipoproteins; Human; Impairment; Incidence; Interruption; Kidney; Kidney Diseases; Link; Lipoproteins; Longitudinal Studies; Mass Spectrum Analysis; Mus; Myocardial Infarction; Names; Nephrectomy; Oxidative Stress; Oxides; Pathogenesis; Pathway interactions; Patients; Peptides; Peroxidases; Physiological; Plasma; Play; Prevalence; Process; Proteins; Proteome; Proteomics; Renal Replacement Therapy; Research Institute; Research Methodology; Research Personnel; Risk; Risk Factors; Role; Rupture; Sampling; Source; Sudden Death; Technology; Testing; Therapeutic; Training; Transgenic Mice; Transplantation; United States; atherogenesis; base; cardiovascular risk factor; clinically significant; disorder risk; experimental study; heart disease risk; heme a; high risk population; in vivo; macrophage; mortality; mouse model; novel marker; novel strategies; overexpression; oxidation; patient population; patient subsets; prevent; prognostic; reverse cholesterol transport; therapy design

ABSTRACT There is a worldwide increase in the incidence and prevalence of chronic kidney disease (CKD) affecting ~11% of adults in the U.S. CKD is a risk factor for CAD, as CKD patients have CAD prevalence of nearly 40% and greater than 10-fold mortality compared to healthy controls. Traditional risk factors are only partially predictive of CAD in CKD subjects, highlighting the need for mechanism-based novel biomarkers that can accurately stratify CAD risk in CKD patients. This proposal directly addresses this critical gap in our diagnostic and prognostic capabilities. We will explore the relationship between CKD, oxidative stress and atherosclerosis in a physiologically relevant animal model with complementary human studies. Evidence strongly implicate a central role for oxidative stress in atherosclerosis but its role in the initiation and progression of CKD- accelerated atherosclerosis has not been systematically investigated. One well-characterized source of oxidative stress is myeloperoxidase (MPO), a heme enzyme that co-localizes with macrophages in human atherosclerotic lesions. While previous studies have attributed MPO oxidation playing a leading role in atherosclerosis, its role in CKD-atherosclerosis has not been systematically elucidated. The overall goals of this proposal are to investigate whether MPO promotes atherogenic risk in CKD. Preliminary studies in a mouse model of CKD strongly demonstrated that MPO oxidative pathway is upregulated in CKD and associated with accelerated atherosclerosis. These observations form the basis of the proposal in which we will test the hypothesis that modulating MPO levels will alter CKD related atherosclerosis in vivo. Together with complementary human studies, we will systematically assess the role of MPO in CKD-accelerated atherosclerosis. The proposed experiments and training plan will enable the PI to gain in depth understanding in cutting edge mass spectrometry and proteomic technologies coupled with intense exposure to vascular biology, transgenic mouse models and clinical research methodology. Specific aims 1) Investigate if MPO plays a central role in CKD-accelerated atherosclerosis mouse models 2) Determine the role of MPO oxidation and lipoprotein profiles in CKD patients with and without CAD These studies will provide evidence for a crucial role for MPO oxidation in the initiation and progression of atherosclerosis in CKD and would facilitate the rational design of interventions to interrupt MPO oxidation.

抽象的 慢性肾脏疾病（CKD）的发生率和患病率在全球范围内增加 美国CKD的成年人中有11％是CAD的危险因素，因为CKD患者的CAD患病率接近40％ 与健康对照相比，死亡率大于10倍。传统的风险因素只是部分 预测CKD受试者中CAD，强调了基于机制的新型生物标志物的需求 准确地分层CKD患者的CAD风险。该建议直接解决了我们诊断中的这一关键差距 和预后能力。我们将探索CKD，氧化应激和动脉粥样硬化之间的关系 在具有互补人类研究的生理相关动物模型中。证据强烈暗示 氧化应激在动脉粥样硬化中的核心作用，但其在CKD-的起始和进展中的作用 尚未系统地研究加速的动脉粥样硬化。一个充分的特征来源 氧化应激是髓过氧化物酶（MPO），一种血红素酶，与人类巨噬细胞共定位 动脉粥样硬化病变。虽然先前的研究归因于MPO氧化在 动脉粥样硬化，其在CKD术中的作用尚未系统地阐明。总体目标 该建议是研究MPO是否促进CKD中的动脉粥样硬化风险。初步研究 CKD的小鼠模型强烈证明MPO氧化途径在CKD和 与加速的动脉粥样硬化有关。这些观察结果构成了我们的提议的基础 将检验以下假设：调节MPO水平将改变体内CKD相关的动脉粥样硬化。一起 互补的人类研究，我们将系统地评估MPO在CKD加速中的作用 动脉粥样硬化。 拟议的实验和培训计划将使PI能够在切割方面获得深入的了解 边缘质谱法和蛋白质组学技术以及强烈接触血管生物学的技术， 转基因小鼠模型和临床研究方法。具体目标 1）研究MPO是否在CKD加速动脉粥样硬化小鼠模型中起核心作用 2）确定MPO氧化和脂蛋白曲线在具有CAD和没有CAD的CKD患者中的作用 这些研究将为MPO氧化在启动和进展中的至关重要作用提供证据 CKD中的动脉粥样硬化，将有助于中断MPO氧化的干预措施的合理设计。