Elucidating the Biology of Cardiovascular Risk in Hemodialysis Patients Using Proteomics

项目摘要 美国有50万名接受血液透析（HD）的终末期肾病（ESRD）患者， 死亡率极高，每年约为18%，其中50%的死亡归因于心血管疾病 心血管疾病（CVD）：即动脉粥样硬化性CVD、心力衰竭和心源性猝死。的有效途径 缺乏对HD人群的预防、治疗和危险分层。医学治疗， 在非ESRD患者中有效，如他汀类药物，在试验中对ESRD患者无效。 随机临床试验。具有讽刺意味的是，传统的心血管疾病危险因素，例如高胆固醇血症、肥胖和 高血压，与这些患者的CVD结局相比， 一般人口。我们的提案中提到的阻碍这些领域取得进展的主要障碍包括： 对HD患者的生物学紊乱了解不足，导致CVD结局不良;和2）失败 将HD人群中的CVD视为一种复杂的、潜在的异质性实体， 使用个体化的CVD模型进行CVD风险分层的个性化方法， 因素是可以改变的。循环蛋白水平可以作为CVD风险的可修改生物标志物，指南 治疗和阐明因果生物途径和机制。我们计划利用先进的 改良的适体检测（SOMAscan），仅在175µl血浆中测量约5000种蛋白质， 灵敏度和特异性。到目前为止，还没有研究利用大规模蛋白质组学来了解结果， 接受HD治疗的ESRD患者的生物学机制。在目标1中，我们建议研究与以下相关的蛋白质： 慢性肾功能不全队列（CRIC）的649名参与者的临床CVD结局， 或更多的研究访问后，开始HD，并验证我们的研究结果，在408名参与者的预测因素 ESRD研究中的心律失常和心血管风险。在目标2中，我们将研究蛋白质的变化， 与频繁血液透析网络中左心室质量的进展或消退相关，以及 在CRIC中验证我们的发现。蛋白质组学将在两个时间点进行测量，间隔1-2年，在2/3的 1324名参与者，以便我们可以研究单个时间点蛋白质以及蛋白质轨迹。我们会委聘 创新方法，包括支持参与者不同基线风险的分层考克斯分析 有和没有CVD，以及风险模型的时间依赖性协变量，以适应 我们对蛋白质变化的分析不可知和有针对性的途径分析将阐明生物网络 在蛋白质预测中。在实现这些目标的过程中，我们将创造准确、个性化和可变的风险 HD患者中CVD事件的模型。我们将鉴定迄今未知的蛋白质和生物途径 与CVD相关;其中一些最终可能成为ESRD干预策略的目标 HD患者，他们非常需要新的治疗方法来改善他们的不良结局。

PROJECT SUMMARY The 500,000 patients in the United States with end-stage renal disease (ESRD) on hemodialysis (HD) suffer extraordinarily high rates of mortality at ~18% per year, with 50% of these deaths attributed to cardiovascular disease (CVD): namely, atherosclerotic CVD, heart failure, and sudden cardiac death. Effective approaches for prevention, treatment and risk stratification in the HD population are lacking. Medical therapies that are effective in patients without ESRD, such as statins, are not beneficial for patients with ESRD when tested in randomized clinical trials. Ironically, traditional CVD risk factors, such as hypercholesterolemia, obesity, and hypertension, have `reverse' associations with CVD outcomes among these patients as compared to the general population. Major obstacles to progress in these areas that are addressed in our proposal include: 1) poor understanding of the disturbed biology in patients on HD that leads to poor CVD outcomes; and 2) failure to consider CVD in the HD population as a complex, potentially heterogeneous entity that calls for a personalized approach to CVD risk stratification using CVD models that are individualized and whose risk factors are modifiable. Circulating protein levels can serve as modifiable biomarkers for CVD risk, guide therapy and elucidate causal biological pathways and mechanisms. We plan to take advantage of an advanced modified aptamer assay (SOMAscan) that measures ~ 5000 proteins in just 175µl of plasma with high sensitivity and specificity. To date, no studies have utilized large-scale proteomics to understand outcomes and biological mechanisms in patients with ESRD on HD. In Aim 1, we propose to study proteins associated with clinical CVD outcomes in 649 participants of the Chronic Renal Insufficiency Cohort (CRIC) who have had one or more study visits after initiation of HD, and validate our findings in 408 participants in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD study. In Aim 2, we will investigate changes in proteins that associate with progression or regression of left ventricular mass in the Frequent Hemodialysis Network, and validate our findings in CRIC. Proteomics will be measured at two time-points 1-2 years apart in 2/3 of the 1324 participants so that we may study single time-point proteins as well as protein trajectories. We will employ innovative methods, including stratified Cox analyses that support differing baseline hazards for participants with and without CVD, and time-dependent covariates for risk models, to accommodate intervening events in our analysis of protein changes. Agnostic and targeted pathway analyses will elucidate biological networks among protein predictors. In carrying out these Aims we will create accurate, personalized and mutable risk models for CVD events in HD patients. We will identify heretofore-unknown proteins and biological pathways associated with CVD; some of these may eventually become targets for interventional strategies for ESRD patients on HD, who are in great need of new therapies to improve their poor outcomes.