Proteomic Approach to CKD Biomarker Discovery and Validation

描述（由申请人提供）： 慢性肾脏病（CKD）是常见的，并与广泛的不良后果相关。两种生物标志物，血清肌酐和白蛋白尿，为大多数CKD患者的分期和风险评估提供了主要依据。临床试验和临床护理都受到这些标记物的限制，并且可以从发现和验证其他标记物中获益。作为对RFA“CKD生物标志物发现和验证联盟”的回应，我们提出了一个创新项目，该项目将生物标志物发现的突破性方法与严格的流行病学，统计学和临床化学专业知识相结合，并应用于四个非常好的特征化队列的深入了解。目标1：生物标志物发现。1. A.重新发现CKD分期的血清滤过标志物。现有技术的蛋白质组学发现方法将鉴定AASK参与者的储存血清中从基线到随访升高> 2倍的蛋白质，所述AASK参与者的测量的GFR从>60下降至<30 ml/min/1.73m2或2倍其血清肌酐。1. B.有针对性地发现CKD进展的尿液和血清损伤标志物。绝对定量质谱法将检测15种最有希望的尿液和血清标志物，以区分100例CKD快速进展为EBRD的病例与100例基线测量GFR相似的对照，这些对照在AASK和MDRD研究中保持稳定。1. C.验证来自1.A的最有希望的标志物。和1 .B在更大的样本量中目标2：生物标志物验证：我们将在整个AASK和MDRD研究人群以及ARIC和NHANES样本中进行的进展性CKD病例对照研究中，测试目标1中确定的最具促进作用的生物标志物，并通过其评估肾功能和CKD进展风险的能力。 我们的研究以肾脏学、生物统计学、流行病学、蛋白质组学、临床化学、合作研究、GFR估计新标志物的近期试点研究以及阿基和CKD相关途径的基因组发现等方面的丰富经验为指导。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is common and associated with a wide range of adverse outcomes. Two biomarkers, serum creatinine and albuminuria, provide the mainstay for staging and risk assessment for the majority of CKD patients. Both clinical trials and clinical care are hampered by the limitations of these markers and could benefit substantially from discovery and validation of additional markers. In reponse to the RFA, "CKD Biomarker Discovery and Validation Consortium", we propose an innovative project that combines breakthrough methods for biomarker discovery with rigorous epidemiological, statistical and clinical chemistry expertise applied with a deep knowledge of four extremely well characterized cohorts. Aim 1: Biomarker Discovery. 1 .A. De novo discovery of serum filtration markers for CKD staging. State of the art proteomic discovery methods will identify proteins with >2x elevation from baseline to follow-up in stored serum of AASK participants whose measured GFR declined from >60 to <30 ml/min/1.73m2 or 2x their serum creatinine. 1 .B. Targeted discovery of urine and serum markers of damage for CKD progression. Absolute quantiation mass spectrometry methods will tests 15 of the most promising urine and serum markers in their ability to distinguish 100 cases with rapid CKD progression to EBRD from 100 controls with similar baseline measured GFR which remained stable from the AASK and MDRD Studies. 1 .C. Verification of the most promising markers from 1 .A. and 1 .B in a larger sample size Aim 2: Biomarker Validation: We will test the most promosing biomarkers identified in aim 1 and through by the consortium in their ability to estimate kidney function and risk of CKD progression in the entire AASK and MDRD Study population and case-control studies of progressive CKD in ARIC and a sample of NHANES. Our studies are guided by extensive experience in nephrology, biostatistics, epidemiology, proteomics, clinical chemistry, collaborative studies, recent pilot studies of novel markers for GFR estimation and genomic discoveries of relevant pathways for AKI and CKD.