Metabolomics Study of APOL1-Associated Chronic Kidney Disease Progression

项目摘要 慢性肾脏病(CKD)是一种常见的疾病，会显著增加终末期肾脏的风险。 疾病(ESKD)和过早死亡。因为CKD通常是进行性的和不可逆转的，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。近期 研究确定了编码载脂蛋白L1(APOL1)基因的两个常见变异，它们导致快速 黑人CKD患者肾功能减退与ESKD的关系然而，更高的 APOL1变异体带来的风险仍不清楚。此外，并不是所有患有APOL1高危人群 基因分型经历了CKD的快速进展。作为内源性和外源性的分子终点 过程中，对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对这一复合体影响的因素 表型。尽管代谢组学研究前景看好，但这一领域的工作仍然很少。总体目标 这一应用的目的是阐明调节和/或改变相互作用的分子机制 载脂蛋白1风险等位基因与慢性肾脏病进展。我们假设对尿液中代谢物的全面研究 CKD患者的样本将辨别APOL1相关CKD进展的生物学途径。我们的 这项研究将利用基线24小时尿样，每年测量肾功能，并严格 对正在进行的慢性病的所有1224名黑人参与者进行长达17年的跟踪调查，判定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APOL1风险改变的代谢物 等位基因(目标1)。然后，我们将检查基线代谢物与慢性肾脏病的预期相关性。 在黑人审评委参与者中取得进展(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中介和修饰作用 协会(目标3)。作为探索性工作，我们将生成一份尿-血浆代谢物目录 利用同时收集的尿液和血浆样本的代谢组学数据在 346名审评委研究参与者(目标4a)。AIMS 1-3中确定的尿代谢物具有中到高度的 将使用558人中的血浆代谢组学数据来评估相关性(在目标4a中)的复制 参加非裔美国人肾脏疾病和高血压研究(目标4b)。拟议中的工作 是首个以载脂蛋白1危险等位基因和慢性肾脏病进展为重点的尿液代谢组学研究。 黑人慢性肾脏病患者。这项在高危人群中进行的创新代谢组学研究可能会揭示出新的 慢性肾脏病进展的机制。我们的发现也可能为发展提供基于证据的目标 预防和逆转慢性肾脏病进展的新的治疗策略。

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.