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: 10664052
• 负责人: Changwei Li
• 金额: $ 25.18万
• 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/10664052
• 关键词: Affect; African American; African ancestry; Alleles; Apolipoproteins; Area; Articulation; 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; adjudication; 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.

项目概要 慢性肾脏病 (CKD) 是一种常见疾病，会显着增加终末期肾病的风险 疾病（ESKD）和过早死亡。由于 CKD 通常是进行性且不可逆转的，因此分子 迫切需要进行研究以更好地了解其病因并确定新的治疗靶点。最近的 研究发现，载脂蛋白 L1 (APOL1) 编码基因中存在两种常见变异，可导致快速 患有 CKD 的黑人患者的肾功能下降和 ESKD。然而，更高层次的机制 APOL1 变体带来的风险仍然未知。此外，并非所有患有 APOL1 高风险的个体 基因型经历快速 CKD 进展。作为内源性和外源性的分子终点 过程中，人类代谢组的检查提供了发现生物途径的机会 将 APOL1 与 CKD 进展联系起来，并确定改变 APOL1 对该复合物影响的因素 表型。尽管代谢组学研究前景广阔，但该领域的工作仍然很少。总体目标 该应用的目的是阐明介导和/或改变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物进行全面研究 CKD 患者样本将辨别 APOL1 相关 CKD 进展的生物学途径。我们的 研究将利用基线 24 小时尿液样本、每年测量的肾功能，并严格 对正在进行的慢性病的所有 1,224 名黑人参与者进行长达 17 年的随访，裁定 CKD 事件 肾功能不全队列 (CRIC) 研究。使用基线 24 小时尿液进行非靶向代谢组学分析 样本将在这些参与者中进行，并用于识别因 APOL1 风险而改变的代谢物 等位基因（目标 1）。然后我们将检查基线代谢物与 CKD 的前瞻性关联 黑人 CRIC 参与者的进步（目标 2）。阐明潜在的分子机制 APOL1 相关的 CKD 进展，我们将评估代谢物对此的调节和调节作用 协会（目标 3）。作为探索性工作，我们将生成尿血浆代谢物目录 通过利用同时收集的尿液和血浆样本的代谢组学数据来确定相关性 346 名 CRIC 研究参与者（目标 4a）。目标 1-3 中鉴定的尿液代谢物具有中度至高度 将使用 558 名患者的血浆代谢组学数据来评估相关性（目标 4a）的复制情况 非裔美国人肾脏疾病和高血压研究（目标 4b）的参与者。拟议的工作 代表第一项专注于 APOL1 风险等位基因和 CKD 进展的尿液代谢组学研究 患有 CKD 的黑人患者。这项针对高危人群的创新代谢组学研究可能会揭示新的 CKD 进展的机制。我们的研究结果还可能为开发提供基于证据的目标 预防和逆转 CKD 进展的新治疗策略。