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: 10001572
• 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 2022-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001572
• 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 全球范围内慢性肾脏病 (CKD) 的发病率和患病率呈上升趋势，影响 美国约 11% 的成年人 CKD 是 CAD 的危险因素，因为 CKD 患者的 CAD 患病率接近 40% 与健康对照组相比，死亡率高出 10 倍以上。传统的风险因素只是部分 预测 CKD 受试者的 CAD，强调需要基于机制的新型生物标志物 准确分层 CKD 患者的 CAD 风险。该提案直接解决了我们诊断中的这一关键差距 和预测能力。我们将探讨 CKD、氧化应激和动脉粥样硬化之间的关系 在具有补充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发挥核心作用，但它在 CKD 的发生和进展中也发挥着重要作用 加速动脉粥样硬化尚未得到系统研究。一种特征明确的来源 氧化应激是髓过氧化物酶（MPO），一种与人类巨噬细胞共定位的血红素酶 动脉粥样硬化病变。虽然之前的研究认为 MPO 氧化在 动脉粥样硬化，其在 CKD 动脉粥样硬化中的作用尚未得到系统阐明。总体目标 该提案旨在调查 MPO 是否会增加 CKD 的动脉粥样硬化风险。初步研究在 CKD 小鼠模型有力地证明了 MPO 氧化途径在 CKD 和 与加速动脉粥样硬化有关。这些意见构成了我们提出的提案的基础 将检验调节 MPO 水平将改变体内 CKD 相关动脉粥样硬化的假设。连同 补充人类研究，我们将系统评估 MPO 在 CKD 加速中的作用 动脉粥样硬化。 所提出的实验和培训计划将使 PI 能够深入了解切削加工 边缘质谱和蛋白质组技术加上对血管生物学的深入了解， 转基因小鼠模型和临床研究方法。具体目标 1) 调查 MPO 是否在 CKD 加速动脉粥样硬化小鼠模型中发挥核心作用 2) 确定 MPO 氧化和脂蛋白谱在患有和不患有 CAD 的 CKD 患者中的作用 这些研究将为 MPO 氧化在疾病发生和进展中的关键作用提供证据。 CKD 中的动脉粥样硬化，将有助于合理设计干预措施以中断 MPO 氧化。