Myeloperoxidase, Chronic Kidney Disease and Atherosclerosis

摘要 慢性肾脏疾病(CKD)的发病率和流行率在全球范围内呈上升趋势。 在美国，约11%的成年人CKD是冠心病的危险因素，因为CKD患者的CAD患病率接近40% 死亡率是健康对照组的10倍以上。传统的风险因素只是部分 预测CKD受试者的CAD，强调了基于机制的新生物标记物的必要性，这种生物标志物可以 准确地对CKD患者的冠心病风险进行分层。该建议直接解决了我们的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、氧化应激与动脉粥样硬化的关系。 在与人体研究互补的生理相关动物模型中。有强有力的证据表明 氧化应激在动脉粥样硬化中的中心作用，但其在慢性肾脏病的发生和发展中的作用 加速的动脉粥样硬化还没有得到系统的研究。一个很好描述的来源 氧化应激是髓过氧化物酶(MPO)，是一种与人类巨噬细胞共存的血红素酶 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，其在慢性肾脏病-动脉粥样硬化中的作用尚未系统阐明。的总体目标 这项建议是为了调查MPO是否增加了CKD的动脉粥样硬化风险。一项初步研究 CKD小鼠模型有力地证明了MPO氧化途径在CKD和CKD中上调。 与加速的动脉粥样硬化有关。这些观察结果构成了提案的基础，在提案中，我们 将在体内验证调节MPO水平将改变CKD相关动脉粥样硬化的假设。与.一起 作为人类研究的补充，我们将系统地评估MPO在CKD加速中的作用 动脉硬化。 建议的实验和培训计划将使PI对切割有更深入的了解 边缘质谱学和蛋白质组学技术，再加上对血管生物学的高强度接触， 转基因小鼠模型及临床研究方法学。具体目标 1)研究MPO在CKD加速的动脉粥样硬化小鼠模型中是否起核心作用 2)测定合并和不合并冠心病的CKD患者MPO氧化和脂蛋白谱的作用 这些研究将为MPO氧化在糖尿病的发生和发展中起关键作用提供证据。 CKD的动脉粥样硬化，将有助于合理设计干预措施以阻断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.