Myeloperoxidase, Chronic Kidney Disease and Atherosclerosis

项目总结/摘要 心血管疾病（CVD）是慢性肾脏疾病（CKD）发病率和死亡率的主要原因， CKD和透析患者的预期寿命减少到一般人的一半到三分之一， 人口然而，慢性肾脏病中加速性心血管疾病的发病机制尚不清楚， 目前可利用特定的治疗策略来减弱这种现象。我们的长期目标是 了解加速动脉粥样硬化的潜在机制，以开发诊断和 治疗方案，以改善CKD患者的寿命。我们的总体目标是确定 髓过氧化物酶在CKD动脉粥样硬化病理生理学中的作用我们的中心假设是， 髓过氧化物酶氧化HDL加速CKD的心血管疾病。我们的理由是，如果 髓过氧化物酶氧化HDL加速CKD动脉粥样硬化，从而开发新的治疗药物 减轻CKD人群CVD负担的策略和生物标志物。我们将测试我们的中央 通过证明髓过氧化物酶氧化对外排能力、HDL蛋白质组和 CKD患者的CVD事件。我们将描述HDL的髓过氧化物酶氧化程度 在348例RRI-CKD患者中使用质谱法，并测试其预测CVD事件的能力。我们也 评估髓过氧化物酶氧化HDL对胆固醇流出能力和HDL蛋白质组的影响。 该项目因COVID-19导致的多个实验室关闭和核心员工延迟而延迟 流行病NHLBI对持续受保护的时间和工资的支持将确保该项目的完成 帮助马修博士建立研究独立性这项研究的创新之处在于， 通过质谱代谢研究HDL蛋白质组的髓过氧化物酶氧化加速CKD中的CVD 和HDL蛋白质组学。这项拟议中的研究意义重大，因为它将提供强有力的证据， 髓过氧化物酶氧化HDL在CKD患者CVD发病机制和预测中的作用， 可能导致临床研究，以预防CKD动脉粥样硬化中的CV事件。

Project Summary/Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in chronic kidney disease (CKD), reducing the life expectancy of CKD and dialysis patients to roughly half to one-third that of the general population. However, the pathogenesis of the accelerated CVD in CKD is not yet clearly understood, and no specific therapeutic strategies are currently available to attenuate this phenomenon. Our long-term goal is to understand the mechanisms underlying accelerated atherosclerosis in order to develop diagnostic and therapeutic solutions to improve the lifespan of patients with CKD. Our overall objective is to define the role of myeloperoxidase in the pathophysiology of CKD atherosclerosis. Our central hypothesis is that the myeloperoxidase oxidized HDL accelerates cardiovascular disease in CKD. Our rationale is that if myeloperoxidase oxidized HDL accelerates CKD atherosclerosis, then we can develop new therapeutic strategies and biomarkers to attenuate the CVD burden in the CKD population. We will test our central hypothesis by demonstrating the role of myeloperoxidase oxidation on the efflux capacity, HDL proteome, and incident CVD events in CKD patients. We will delineate the extent of myeloperoxidase-based oxidation of HDL using mass spectrometry in 348 patients of the RRI-CKD and test their ability to predict CVD events. We also evaluate the effect of myeloperoxidase oxidized HDL on cholesterol efflux capacity and the HDL proteome. This project was delayed by the multiple lab closures and core staff delays caused by the COVID-19 pandemic. Support from the NHLBI for continued protected time and salary will ensure this project's completion and help establish Dr. Mathew's research independence. The proposed research is innovative in that it links myeloperoxidase oxidation of the HDL proteome to accelerated CVD in CKD via mass spectrometric metabolic profiling and HDL proteomics. The proposed research is significant because it will provide strong evidence of the role of myeloperoxidase oxidized HDL in the pathogenesis and prediction of CVD in CKD patients, potentially leading to clinical studies to prevent CV events in CKD atherosclerosis.