Metabolomics Study of APOL1-Associated Chronic Kidney Disease Progression

APOL1 相关慢性肾病进展的代谢组学研究

• 批准号: 10504813
• 负责人: Changwei Li
• 金额: $ 25.43万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504813
• 关键词: Affect; African American; African ancestry; Alleles; Apolipoproteins; Area; Biological; Black Populations; Black race; Bladder; Cardiometabolic Disease; Catalogs; Centers of Research Excellence; Cessation of life; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical Research; Cohort Studies; Complex; Cox Proportional Hazards Models; Data; Development; Disease Progression; End stage renal failure; Environment; Equation; Etiology; Event; Foundations; Funding; Genes; Genetic Models; Genotype; Glomerular Filtration Rate; Hour; Human; Hypertension; Individual; Kidney; Kidney Diseases; Linear Regressions; Link; Measures; Mediating; Mediation; Metabolic Pathway; Modeling; Molecular; Nephrons; Participant; Pathway interactions; Patients; Persons; Phenotype; Plasma; Population; Precision Health; Process; Public Health; Publishing; Renal function; Research; Research Personnel; Risk; Sampling; Testing; Therapeutic; Translational Research; Urine; Variant; Work; adjudicate; base; bioinformatics tool; black patient; clinically significant; cohort; disorder prevention; evidence base; experience; follow-up; functional decline; genomic data; high risk; high risk population; innovation; metabolome; metabolomics; multidisciplinary; new therapeutic target; novel; novel therapeutic intervention; premature; prevent; programs; prospective; racial disparity; recessive genetic trait; risk variant; urinary

Project Summary Chronic kidney disease (CKD) is a common condition that significantly increases risks for end stage kidney disease (ESKD) and premature death. Because CKD is generally progressive and irreversible, molecular research to better understand its etiology and identify novel therapeutic targets is critically needed. Recent studies identified two common variants in the gene encoding apolipoprotein L1 (APOL1) that cause rapid kidney function decline and ESKD in Black patients with CKD. However, the mechanisms underlying the higher risk conferred by the APOL1 variants are still unknown. In addition, not all individuals with the high risk APOL1 genotype experience rapid CKD progression. As the molecular endpoint of endogenous and exogenous processes, examination of the human metabolome provides an opportunity to discover biological pathways linking APOL1 to CKD progression and identify factors that modify the effects of APOL1 on this complex phenotype. Despite the promise of metabolomics study, work in this area remains sparse. The overall objective of this application is to elucidate molecular mechanisms that mediate and/or modify the association between APOL1 risk alleles and CKD progression. We hypothesize that a comprehensive study of metabolites in urinary samples of CKD patients will discern biological pathways underlying APOL1-associated CKD progression. Our study will leverage baseline 24-hour urine samples, annually measured kidney function, and stringently adjudicated CKD events in up to 17 years follow-up among all 1,224 Black participants of the ongoing Chronic Renal Insufficiency Cohort (CRIC) Study. Untargeted metabolomics profiling using baseline 24-hour urine samples will be conducted among these participants and used to identify metabolites altered by APOL1 risk alleles (Aim 1). We will then examine the prospective associations of baseline metabolites with CKD progression among the Black CRIC participants (Aim 2). To articulate the molecular mechanisms underlying APOL1-associated CKD progression, we will assess the mediating and modifying effects of metabolites on this association (Aim 3). As exploratory work, we will generate a catalogue of urinary-plasma metabolite correlations by leveraging metabolomics data from simultaneously collected urine and plasma samples among 346 CRIC study participants (Aim 4a). Urinary metabolites identified in Aims 1-3 that have a moderate-to-high correlation (in Aim 4a) will be evaluated for replication using plasma metabolomics data among 558 participants of the African American Study of Kidney Disease and Hypertension (Aim 4b). The proposed work represents the first urinary metabolomics study focusing on APOL1 risk alleles and CKD progression among Black patients with CKD. This innovative metabolomics study among a high-risk group is likely to reveal novel mechanisms of CKD progression. Our findings may also provide evidence-based targets for the development of novel therapeutic strategies to prevent and reverse CKD progression.

项目摘要 慢性肾脏疾病（CKD）是一种常见疾病，可显着增加末期肾脏的风险 疾病（ESKD）和过早死亡。因为CKD通常是渐进的和不可逆的，所以分子 需要进行更好地了解其病因并确定新型治疗靶标的研究。最近的 研究确定了编码载脂蛋白L1（APOL1）的基因中的两个常见变体，这些变体引起了快速 黑人CKD患者的肾功能下降和ESKD。但是，较高的机制 APOL1变体赋予的风险仍然未知。此外，并非所有具有高风险APOL的人 基因型经历快速CKD进展。作为内源性和外源性的分子终点 过程，对人代谢组的检查提供了发现生物学途径的机会 将apol1链接到ckd的进展并确定改变apol1对该复合物的影响的因素 表型。尽管有代谢组学研究的希望，但该领域的工作仍然很少。总体目标 该应用的是阐明介导和/或修改之间关联的分子机制 Apol1风险等位基因和CKD进展。我们假设对尿中代谢产物的全面研究 CKD患者的样本将辨别与APOL1相关的CKD进展的生物学途径。我们的 研究将利用基线24小时的尿液样本，每年测量的肾功能以及严格的 在正在进行的所有1,224名黑人参与者中，最多17年的随访中裁定的CKD事件正在进行 肾功能不全队列（CRIC）研究。使用基线24小时尿液的非靶向代谢组学分析 样本将在这些参与者中进行，并用于识别APOL1风险改变的代谢产物 等位基因（目标1）。然后，我们将检查基线代谢产物与CKD的前瞻性关联 黑色CRIC参与者的进展（AIM 2）。阐明基础机制 与Apol1相关的CKD进展，我们将评估代谢物对此的介导和修饰作用 协会（目标3）。作为探索性工作，我们将生成尿等流质代谢物的目录 通过利用来自同时收集的尿液和血浆样品的代谢组学数据的相关性 346个CRIC研究参与者（AIM 4A）。 AIMS 1-3中鉴定出的尿代谢产物中等高度 相关性（在AIM 4A中）将在558中使用血浆代谢组数据进行评估以进行复制 非裔美国人对肾脏疾病和高血压研究的参与者（AIM 4B）。拟议的工作 代表着第一个关注APOL1风险等位基因和CKD进展的第一个尿代谢组学研究 黑人患者CKD。在高风险群体中，这项创新的代谢组学研究可能揭示了新颖的 CKD进展的机制。我们的发现还可能为开发提供基于证据的目标 预防和逆转CKD进展的新型治疗策略。