Myeloperoxidase, Chronic Kidney Disease and Atherosclerosis

摘要 慢性肾脏疾病（CKD）的发病率和患病率在全球范围内增加， 美国约11%的成人CKD是CAD的风险因素，因为CKD患者的CAD患病率接近40% 死亡率是健康对照组的10倍。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。我们将探讨慢性肾脏病，氧化应激和动脉粥样硬化之间的关系 在生理学相关的动物模型中进行补充人体研究。有证据表明 氧化应激在动脉粥样硬化中的核心作用，但在CKD的启动和进展中的作用， 加速的动脉粥样硬化尚未被系统地研究。一个特征鲜明的 氧化应激是髓过氧化物酶（MPO），一种与人体巨噬细胞共定位的血红素酶 动脉粥样硬化病变虽然以前的研究认为MPO氧化在糖尿病中起主导作用， 尽管其在CKD-动脉粥样硬化中的作用尚未被系统地阐明。的总目标 本研究旨在研究MPO是否促进CKD患者的动脉粥样硬化风险。初步研究， CKD小鼠模型强烈表明MPO氧化途径在CKD中上调， 与加速动脉粥样硬化有关。这些意见构成了建议的基础， 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 补充人体研究，我们将系统地评估MPO在CKD加速中的作用， 动脉粥样硬化 建议的实验和培训计划将使PI在切割中获得深入的理解 边缘质谱和蛋白质组学技术加上对血管生物学的强烈暴露， 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加速的动脉粥样硬化小鼠模型中起核心作用 2)确定MPO氧化和脂蛋白谱在伴和不伴CAD的CKD患者中的作用 这些研究将为MPO氧化在肝硬化的发生和发展中的关键作用提供证据。 CKD中动脉粥样硬化的发生率，并将促进干预的合理设计，以中断MPO氧化。

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.