Proteomic Markers of Arteriosclerosis

描述（由申请人提供）： 申请人的长期目标是开发新的、经验证的生物标志物，以实现血管疾病的早期检测。美国有超过6500万人患有高血压。动脉炎（即，动脉粥样硬化和小动脉硬化）在高血压的情况下加速，并导致靶器官损伤， 心血管后遗症，如中风、心肌梗死、慢性肾功能不全和跛行。目前可用的风险评估工具的敏感性和特异性较差。验证动脉血管疾病的新生物标志物将允许制定创新的预防和治疗策略，以最终提高生活质量并降低死亡率。本申请建议调查 非裔美国人炎症、血栓形成、脂蛋白代谢、血管重塑和氧化应激途径中的50个候选蛋白质组学标志物与动脉硬化4种不同定量指标的关系（n = 1150）和非西班牙裔白色人（n = 1150）属于高血压同胞的个体，利用作为NHLBI家庭血压计划的一部分开发的优秀临床研究基础设施。动脉粥样硬化或“大血管”疾病的措施包括踝肱指数和冠状动脉钙化的数量。可用于该建议的小动脉硬化或“微血管”疾病的测量包括通过脑磁共振成像和尿白蛋白-肌酐比值评估的脑白质疏松。我们将实现以下具体目标：具体目标1：我们将为50个候选蛋白质组标志物开发稳健的经验证的检测方法，并使用经验证的检测方法，测量属于两个种族队列的2300名受试者的蛋白质组标志物。我们还将开发和验证用于多重检测的6-8个标记的面板。 具体目标二：我们将使用各种统计方法，包括主成分因子分析和（贝叶斯和非贝叶斯）模型平均，以确定属于两个种族队列的2300名受试者中动脉硬化的4种定量指标中每一种的最佳预测模型（从50种蛋白质组标志物中）。

DESCRIPTION (provided by applicant): The long term goal of the applicant is to develop new, validated biomarkers that will enable early detection of vascular disease. More than 65 million people in the United States are affected by hypertension. Arteriosclerosis (i.e., atherosclerosis and arteriolosclerosis) of the cerebral, cardiac, renal, and peripheral arterial beds is accelerated in the setting of hypertension and leads to target organ damage and cardiovascular sequelae such as stroke, myocardial infarction, chronic renal insufficiency, and claudication. Currently available risk assessment tools have poor sensitivity and specificity. Validating new biomarkers of arteriosclerotic vascular disease will allow formulation of innovative preventive and therapeutic strategies to ultimately improve quality-of-life and reduce mortality. This application proposes to investigate the relationship of 50 candidate proteomic markers in pathways of inflammation, thrombosis, lipoprotein metabolism, vascular remodeling, and oxidative stress to 4 different quantitative measures of arteriosclerosis in African American (n = 1150) and non-Hispanic white (n = 1150) individuals belonging to hypertensive sibships, leveraging the excellent clinical research infrastructure developed as part of the NHLBI's Family Blood Pressure Program. The measures of atherosclerotic or 'macrovascular' disease available for this proposal include the ankle-brachial index and quantity of coronary artery calcification. The measures of arteriolosclerotic or 'microvascular' disease available for this proposal include cerebral leukoaraiosis assessed by magnetic resonance imaging of the brain and urinary albumin-creatinine ratio. We will accomplish the following specific aims: Specific Aim 1: We will develop robust validated assays for 50 candidate proteomic markers and using the validated assays, measure the proteomic markers in 2300 subjects belonging to the two ethnic cohorts. We will also develop and validate panels of 6-8 markers for multiplex assays. Specific Aim 2: We will use a variety of statistical approaches including Principal Components Factor Analysis and (Bayesian and non-Bayesian) model-averaging to identify the best predictive models (from among the 50 proteomic markers) for each of the 4 quantitative measures of arteriosclerosis in the 2300 subjects belonging to the two ethnic cohorts.