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（由适用提供）：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在于各种代谢性疾病的交汇处，因为肾功能对循环代谢产物具有广泛的影响，并且由于循环代谢物可能自己参与疾病的病原体病原体。我们建议对从慢性肾功能不全队列（CRIC）研究中的研究进入时进行液态色谱，基于质谱的代谢产物分析，目的是发现新型CKD进展的基于血液的生物标志物；了解这些代谢物与估计的肾小球滤过率（EGFR），蛋白尿水平和其他CKD表型的横截面关联；并将代谢物数据与已经执行的基因分型整合在一起。 AIM 1将使用多变量COX回归来检查基线代谢物水平与终末期肾脏疾病的复合时间结果或EGFR减半的关系。我们将检验以下假设：降低色氨酸和精氨酸水平以及cAMP升高是CKD进展的标志，并且对所有测得的代谢物水平进行不可知论检查。 AIM 2将评估血浆代谢物在CKD严重程度（EGFR和蛋白尿水平）的水平以及CKD中现有代谢无序代谢标记的关系方面如何变化。 AIM 3将进行一项基因组广泛的关联研究（GWAS），以鉴定AIM 1和2中突出显示的CKD和CKD进展的代谢物生物标志物的因果决定剂，并评估这些标记是否受到以前与CKD相关的基因基因座调节。这些研究将允许评估新颖的标志物是否属于催化途径，并且与先前的代谢组学不同，GWAS将检查富含CKD及其代谢前因的大致多样化的种群。除了这些科学目标外，在AIM 4中，我们试图建立CRIC作为验证新颖的平台生物标志物被发现是更广泛的CKD生物标志物联盟工作的一部分。通过广泛的研究数据和对CKD及其并发症的明确关注，CRIC研究的独特位置可以催化提案的每个组成部分，CRIC指导委员会强烈致力于丰富更广泛的财团活动。重要的是，跨肾脏疾病的初步研究表明所有既定目标的可行性。此外，该提案结合了技术的改进，这些改进已大大提高了我们的代谢组学平台的广度，包括〜350个已知代谢产物和> 5000个未知代谢物峰，从而扩大了我们先前研究以外调查的代谢物的范围。最后，所有数据都将通过DBGAP公开，就像我们小组生成的先前代谢组学和GWAS数据一样，为研究社区提供了强大的资源。