Metabolomics Study of APOL1-Associated Chronic Kidney Disease Progression

项目摘要 慢性肾病（CKD）是一种常见的疾病，可显著增加终末期肾病的风险。 疾病（ESKD）和过早死亡由于CKD通常是进行性和不可逆的，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 研究确定了编码载脂蛋白L1（APOL 1）的基因中的两种常见变体， 黑人CKD患者肾功能下降和ESKD。然而，更高的潜在机制 APOL 1变异体带来的风险仍然未知。此外，并非所有具有高风险APOL 1的个体 基因型患者CKD进展迅速。作为内源性和外源性 过程，检查人体代谢组提供了一个机会，发现生物途径 将APOL 1与CKD进展联系起来，并确定修饰APOL 1对该复合物影响的因素 表型。尽管代谢组学研究的前景，在这方面的工作仍然稀少。总体目标 本申请的目的是阐明介导和/或改变 APOL 1风险等位基因与CKD进展我们假设，对尿中代谢物的全面研究 CKD患者的样本将辨别APOL 1相关CKD进展的生物学途径。我们 研究将利用基线24小时尿液样本，每年测量肾功能，并严格 在所有1，224名正在进行的慢性肾脏病研究的黑人参与者中， 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 将在这些受试者中进行样本采集，并用于鉴定APOL 1风险改变的代谢物 等位基因（Aim 1）。然后，我们将研究基线代谢物与CKD的前瞻性关联 在黑人CRIC参与者中取得进展（目标2）。为了阐明潜在的分子机制 APOL 1相关的CKD进展，我们将评估代谢产物对此的介导和修饰作用。 （目标3）。作为探索性工作，我们将生成尿液-血浆代谢物目录 通过利用来自同时收集的尿液和血浆样本的代谢组学数据， 346名审评委研究参与者（目标4a）。在目标1-3中鉴别的具有中度至高度 将使用558名受试者的血浆代谢组学数据评价复制相关性（目标4a）。 非裔美国人肾病和高血压研究（Aim 4 b）的参与者。拟议工作 代表了第一项尿代谢组学研究，重点关注APOL 1风险等位基因和CKD进展， CKD黑人患者。这项在高危人群中进行的创新性代谢组学研究可能会揭示新的 CKD进展的机制。我们的研究结果也可能为发展提供基于证据的目标 预防和逆转CKD进展的新治疗策略。

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.