Metabolomics of CKD and CKD Progression

CKD 和 CKD 进展的代谢组学

基本信息

批准号：
8976919
负责人：
EUGENE P. RHEE
金额：
$ 44.71万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-14 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976919
关键词：
Advanced Glycosylation End Products Affect Albumins Arginine Biological Biological Markers Biology Blood Cardiovascular system Cessation of life Chronic Kidney Failure Chronic Kidney Insufficiency Clinical Clinical Data Cohort Studies Communities Cyclic AMP Data Diabetes Mellitus Dialysis patients Disease Disease Progression End stage renal failure Epidemiology Event Fibroblast Growth Factor Genes Genetic Genetic Determinism Genotype Glomerular Filtration Rate Goals Heterogeneity Human Genetics Individual Insulin Interleukin-6 Investigation Kidney Kidney Diseases Kidney Failure Link Lipids Measures Metabolic Metabolic Diseases Methods Obesity Outcome Pathogenesis Pathway interactions Phenotype Pilot Projects Plasma Population Heterogeneity Population Study Positioning Attribute Proteinuria Renal function Research Resolution Resource Allocation Resources Risk Sampling Severity of illness Surveys Testing Time Tryptophan Urine Validation base clinical care cohort disease diagnosis disease phenotype drug development genome wide association study improved inorganic phosphate insight interest liquid chromatography mass spectrometry metabolomics novel novel marker outcome forecast public health relevance small molecule

项目摘要

DESCRIPTION (provided by applicant): A systematic survey of the plasma metabolome is a promising approach for CKD biomarker research because CKD lies at the intersection of various metabolic disorders, because of the broad impact renal function has on circulating metabolites, and because circulating metabolites may themselves participate in disease pathogenesis. We propose to perform liquid chromatography, mass spectrometry based metabolite profiling on plasma obtained at study entry from 1800 individuals in the Chronic Renal Insufficiency Cohort (CRIC) Study with the goal to discover novel blood-based biomarkers of CKD progression; to understand the cross- sectional association of these metabolites with estimated glomerular filtration rate (eGFR), level of proteinuria, and other CKD phenotypes; and to integrate the metabolite data with genotyping that has already been performed. Aim 1 will use multivariable Cox regression to examine the relation between baseline metabolite levels and a composite time-to-event outcome of end-stage renal disease or halving of eGFR. We will test the hypothesis that decreased tryptophan and arginine levels and increased cAMP levels are markers of CKD progression, as well as conduct an agnostic examination of all measured metabolite levels. Aim 2 will assess how plasma metabolites vary across levels of CKD severity (eGFR and level of proteinuria) and in relation to existing markers of disordered metabolism in CKD (albumin, clinical lipids, insulin, advanced glycation end- products, PTH, FGF-23, phosphate, hsCRP, and IL-6). Aim 3 will perform a genome wide association study (GWAS) to identify causal determinants of metabolite biomarkers of CKD and CKD progression highlighted in Aims 1 and 2, and to assess whether these markers are modulated by genetic loci that have previously been associated with CKD. These studies will permit assessment of whether novel markers belong to causal pathways, and unlike prior metabolomics GWAS would examine a racially diverse population enriched for CKD and its metabolic antecedents. In addition to these scientific objectives, in Aim 4 we seek to establish CRIC as a platform for the validation of novel biomarkers discovered as part of the wider CKD Biomarker Consortium efforts. With extensive study data and an explicit focus on CKD and its complications, the CRIC Study is uniquely positioned to catalyze each component of the proposal, and the CRIC Steering Committee is strongly committed to enriching the broader consortium activities. Importantly, preliminary studies across a spectrum of renal disease demonstrate feasibility for all of the stated Aims. Further, the proposal incorporates technological improvements that have dramatically increased the breadth of our metabolomics platform to now include ~350 known metabolites and >5000 unknown metabolite peaks, thus expanding the scope of metabolites surveyed beyond our prior studies. Finally, all data will be made public via dbGAP as with prior metabolomics and GWAS data generated by our group, providing a powerful resource for the research community.

描述（由申请人提供）：血浆代谢组的系统调查是 CKD 生物标志物研究的一种有前途的方法，因为 CKD 位于各种代谢紊乱的交叉点，因为肾功能对循环代谢物具有广泛的影响，并且因为循环代谢物可能我们建议对 1800 名慢性肾病患者的血浆进行基于液相色谱、质谱的代谢物分析。功能不足队列 (CRIC) 研究，旨在发现 CKD 进展的新型血液生物标志物；了解这些代谢物与估计肾小球滤过率 (eGFR)、蛋白尿水平和其他 CKD 表型的横截面关联；将代谢物数据与已执行的基因分型相结合，目标 1 将使用多变量 Cox 回归来检查基线代谢物水平和复合物之间的关系。我们将检验以下假设：色氨酸和精氨酸水平降低以及 cAMP 水平升高是 CKD 进展的标志，并对所有测量的代谢物水平进行不可知的检查。目标 2 将评估血浆代谢物如何随 CKD 严重程度（eGFR 和蛋白尿水平）的变化而变化，以及与 CKD 代谢紊乱的现有标志物（白蛋白、临床Aim 3 将进行全基因组关联研究 (GWAS)，以确定 CKD 和 CKD 进展的代谢生物标志物的因果决定因素。目标 1 和 2 中强调的，并评估这些标记是否受到先前与 CKD 相关的基因位点的调节。这些研究将允许评估新标记是否属于因果途径，与之前的代谢组学不同，GWAS 将检查富含 CKD 的种族多样化人群及其代谢前因。除了这些科学目标之外，在目标 4 中，我们还寻求建立 CRIC 作为验证新药物的平台。作为更广泛的 CKD 生物标志物联盟工作的一部分而发现的生物标志物，凭借广泛的研究数据和对 CKD 及其并发症的明确关注，CRIC 研究具有独特的地位，可以促进该提案的各个组成部分，并且 CRIC 指导委员会致力于丰富内容。重要的是，针对一系列肾脏疾病的初步研究证明了所有上述目标的可行性。此外，该提案还纳入了技术改进，极大地扩大了我们代谢组学的广度。平台目前包括约 350 种已知代谢物和超过 5000 种未知代谢物峰，从而将调查的代谢物范围扩大到我们之前的研究之外。最后，与我们小组之前生成的代谢组学和 GWAS 数据一样，所有数据都将通过 dbGAP 公开。研究界的强大资源。