Elucidating the Biology of Cardiovascular Risk in Hemodialysis Patients Using Proteomics

利用蛋白质组学阐明血液透析患者心血管风险的生物学

基本信息

批准号：
10700128
负责人：
Ruth Dubin
金额：
$ 72.15万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700128
关键词：
Address Age Area Arrhythmia Atherosclerosis Biological Biological Assay Biological Markers Biology Blood specimen Cardiac Cardiovascular Diseases Cardiovascular Models Cardiovascular system Cessation of life Chronic Kidney Failure Chronic Kidney Insufficiency Clinical Complex Controlled Clinical Trials Dialysis procedure Disease Outcome Disease model EFRAC Echocardiography Effectiveness End stage renal failure Ethnic Origin Event Failure General Population Goals Heart failure Hemodialysis Hospitalization Hypertension Individual Intervention Left Ventricular Mass Life Style Magnetic Resonance Measures Medical Medicare Methods Modeling Morbidity - disease rate Myocardial Infarction Obesity Outcome Participant Pathway Analysis Pathway interactions Patient-Focused Outcomes Patients Placebo Control Plasma Population Prevention approach Protein Analysis Proteins Proteome Proteomics Protocols documentation Public Health Race Regimen Renal function Risk Risk Factors Sampling Sensitivity and Specificity Testing Therapeutic Time United States Visit Vulnerable Populations adjudication adverse outcome aptamer beneficiary cardiovascular disorder risk cardiovascular risk factor cerebrovascular cohort hazard high risk hypercholesterolemia improved innovation insight mortality new therapeutic target novel novel therapeutics patient stratification personalized approach pointed protein preservation prospective protein biomarkers randomized, clinical trials risk stratification sex sudden cardiac death therapeutic target treatment stratification

项目摘要

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.

项目摘要美国血液透析（HD）患者的500,000名患有终末期肾脏疾病（ESRD）的患者每年约18％的死亡率非常高，其中50％归因于心血管疾病（CVD）：即动脉粥样硬化CVD，心力衰竭和心脏猝死。有效的方法缺乏高清人群中的预防，治疗和风险分层。医疗疗法在没有ESRD的患者（例如他汀类药物）中有效，对ESRD的患者无益随机临床试验。具有讽刺意味的是，传统的CVD危险因素，例如高胆固醇血症，肥胖和与这些患者中的CVD结局有高血压，与这些患者的CVD结局有“反向”关联。一般人口。在我们的提案中解决的这些领域中进步的主要障碍包括：1）在HD患者中对受影响的生物学的了解不足，导致CVD结果差； 2）失败将HD人口中的CVD视为一个复杂的，潜在的异质实体，要求使用个性化且风险的CVD模型的个性化方法进行CVD风险分层因素是可修改的。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学途径和机制。我们计划利用高级修改的APATMER分析（SOMASCAN），仅在175µL血浆中测量约5000蛋白灵敏度和特异性。迄今为止，尚无研究使用大规模蛋白质组学来了解结果和 HD上ESRD患者的生物学机制。在AIM 1中，我们建议研究与慢性肾功能不全队列（CRIC）的649名参与者的临床CVD结果或启动高清后的更多研究访问，并在408位参与者中验证我们的发现 ESRD研究中的心律失常和心血管风险。在AIM 2中，我们将调查蛋白质的变化与频繁的血液透析网络中左心室质量的进展或回归相关，验证我们在Cric中的发现。蛋白质组学将在2/3的2/3相距1-2年以两个时间点进行测量 1324名参与者，以便我们可以研究单个时间点蛋白以及蛋白质轨迹。我们将雇用创新方法，包括支持参与者区分基线危害的分层COX分析有或没有CVD，以及风险模型的时间依赖性协变量，以适应中间事件我们对蛋白质变化的分析。不可知论和有针对性的途径分析将阐明生物网络在蛋白质预测因子中。在执行这些目标时，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。我们将确定迄今未知的蛋白质和生物学途径与CVD相关；其中一些有时可能成为ESRD介入策略的目标高清患者非常需要新的疗法来改善其不良结果。