U Maryland Mid-Atlantic APOLLO Research Network Omic and Clinical Center

项目摘要 在非裔美国人（AA）中发现的某些APOL 1基因变异表明，这些变异 是慢性肾病（CKD）发展的主要原因。事实上，某些APOL 1基因变体 与欧洲相比，AA中终末期肾病（ESRD）的显著增加主要是由于 美国人（EA）。此外，具有这些相同APOL 1基因变异的肾移植具有双重的免疫抑制作用。 增加失败。因此，重要的是要了解这些APOL 1基因如何有助于肾移植 肾功能衰竭，并找到其他因素，可以增加或减少这种肾功能衰竭的发生。还有 需要了解某些APOL 1基因是否会影响活着的AA肾脏捐赠者的健康。NIDDK APOLLO网络是产生回答这些重要问题所需数据的关键一步。我们 在大西洋中部建立了一个多个移植项目的网络， 研究人员将收集一大群AA肾脏捐赠者和接受者，以跟踪他们的健康和肾脏 功能随着时间的推移，以及建立一个肾脏组织，血清和尿液生物库，提供一个平台， 有希望的未来研究。 某些APOL 1基因变异如何影响肾功能的机制尚不清楚。 因此，我们建议利用最先进的“组学”技术，如RNA测序、外显子组测序、基因组测序和基因组测序。 对肾脏活检、血清和尿液样本进行代谢组学和表观遗传学测序， APOL 1基因变异如何导致肾脏疾病我们将把这些测试的结果与 捐赠者和接受者以及他们的肾脏功能。 我们提出了三个主要假设：（1）。AA中的某些APOL 1基因变体可以激活 导致肾脏异常反应的途径，导致肾脏CKD易感性增加 捐助者; 2.在肾脏接受者中，某些APOL 1基因变体可激活导致肾损伤的反应 和增加的CKD和/或肾移植失败;和3.）某些APOL 1基因变体可以刺激 肾脏反应异常，导致供体或受体血压升高和心脏病。 为了验证这些假设，我们提出了三个目标：目标1：（a）建立一个大的AA活体肾组 供体;（B）建立血清和尿液生物库;和（c）检查APOL 1基因与 肾脏疾病目的2：（a）建立一个大的AA肾受体组;（B）建立肾活检， 血清和尿液生物库;（c）确定APOL 1基因与移植结果之间的关系;（d） 检查APOL 1基因与肾活检病理学的关系;以及（e）使用基于组学的 APOL 1基因变异如何影响肾脏预后。目标3：（a）评估关系 APOL 1基因变异与心脏病之间的关系。

Project Summary The discovery of certain APOL1 gene variations in African Americans (AA) showed that these variants are a major reason for the development of chronic kidney disease (CKD). Indeed, certain APOL1 gene variants account for much of the striking increase in end-stage renal disease (ESRD) in AA compare to European Americans (EA). In addition, kidney transplants that have these same APOL1 gene variants have a two-fold increase for failure. Thus, it is important to understand how these APOL1 genes contribute to kidney transplant failure and find other factors that can increase or decrease the occurrence of such kidney failure. There is also a need to understand if certain APOL1 genes will affect the health of living AA kidney donors. The NIDDK APOLLO network is a critical step in generating the data needed to answer these important questions. We have assembled a network of multiple transplant programs in the Mid-Atlantic and a multidisciplinary team of investigators that will gather a large group of AA kidney donors and recipients to follow their health and kidney function over time, as well as build a kidney tissue, serum and urine biobank to provide a platform for promising additional future research. The mechanisms of how certain APOL1 gene variants affect kidney function are not known. Accordingly, we propose to utilize state of the art “omics” technologies such as RNA sequencing, exome sequencing metabolomics and epigenetics on the kidney biopsies, sera and urine samples to help discover how APOL1 gene variants cause kidney diseases. We will correlate the results of these tests with the health of the donors and recipients and the function of their kidneys. We propose to test three primary hypotheses: 1.) Certain APOL1 gene variants in AA can activate pathways that lead to abnormal responses in kidneys, resulting in increased susceptibility to CKD in kidney donors; 2.) In kidney recipients, certain APOL1 gene variants can activate responses that lead to kidney injury and increased CKD and/or kidney transplant failure; and 3.) Certain APOL1 gene variants can stimulate abnormal kidney responses, leading to increased blood pressure and cardiac disease in donors or recipients. To test these hypotheses we propose three aims: Aim 1: (a) Establish a large group of AA live kidney donors; (b) Establish a serum and urine biobank; and (c) Examine the relationship between APOL1 genes and kidney diseases. Aim 2: (a) Establish a large group of recipients of AA kidneys; (b) Establish kidney biopsy, serum and urine biobank; (c) Determine the relationship between APOL1 genes and transplant outcomes; (d) Examine the relationship of APOL1 genes and the pathology of the kidney biopsies; and (e) Use omics based methods to identify how APOL1 gene variants affect kidney outcomes. Aim 3: (a) Assess the relationship between of APOL1 gene variants and cardiac disease.