Proteomic Approach to CKD Biomarker Discovery and Validation

描述(由申请人提供)： 慢性肾脏疾病(CKD)很常见，并与一系列不良后果相关。两个生物标志物，血清肌酐和蛋白尿，为大多数CKD患者的分期和风险评估提供了支柱。临床试验和临床护理都受到这些标记物的限制，并可能从其他标记物的发现和验证中受益匪浅。为了响应RFA，“CKD生物标记物发现和验证联盟”，我们提出了一个创新项目，将生物标记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结合起来，并深入了解四个极具特征的队列。目标1：发现生物标记物。1.新发现用于CKD分期的血清滤过标志物。最先进的蛋白质组发现方法将在AASK参与者的储存血清中识别出从基线到后续的&gt；2倍升高的蛋白质，这些参与者测得的GFR从&gt；60下降到&lt；30ml/min/1.73m2或他们的血清肌酐水平的2倍。1.有针对性地发现CKD进展的尿液和血清损伤标志物。绝对定量质谱法将测试15个最有希望的尿液和血清标记物的能力，以区分100例快速发展为EBRD的CKD患者和100例基线测量GFR相似的对照组，AASK和MDRD研究结果保持稳定。1.c.在更大的样本量中验证来自1.A.和1.b的最有希望的标记目标2：生物标记验证：我们将测试Aim 1中和通过该联盟确定的最具促进作用的生物标记物在整个AASK和MDRD研究人群中评估肾功能和CKD进展风险的能力，以及ARIC和NHANES样本中进行性CKD的病例对照研究。我们的研究以肾病学、生物统计学、流行病学、蛋白质组学、临床化学、合作研究、最近用于评估GFR的新标记物的初步研究以及AKI和CKD相关通路的基因组发现为指导。 公共卫生相关性：慢性肾脏疾病很常见，通常根据血液和尿液标记物进行分期。目前，血肌酐和尿白蛋白是应用最广泛的慢性肾脏疾病患者分期和预后的生物标志物。我们建议加入一个联盟，该联盟的目标是发现和验证更多的标记物，这些标记物将改善患者护理并促进慢性肾脏疾病的研究。

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. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is common and usually stages by blood and urine markers. Currently serum creatinine and urinary albumin at the most widely used biomarkers for staging and prognosis of patients with chronic kidney disease. We propose to join a consortium whose goal is to discover and validate additional markers which will improve patient care and faciliate research in chronic kidney disease.