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

马里兰大学大西洋中部阿波罗研究网络组学和临床中心

• 批准号: 9975149
• 负责人: Jonathan S Bromberg
• 金额: $ 13.33万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975149
• 关键词: APOL1 gene; Acute; Affect; African American; Albuminuria; Allografting; American; Antibodies; Biochemical; Biological Markers; Biopsy Specimen; Biotechnology; Blood Pressure; Cardiovascular system; Chronic Kidney Failure; Clinical; Data; Development; End stage renal failure; Epigenetic Process; European; Event; Failure; Functional disorder; Future; Genes; Genotype; Glomerular Filtration Rate; Health; Heart Diseases; Histologic; Hypertension; Injury to Kidney; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Lead; Living Donors; Longitudinal cohort; Maryland; Mediating; Metabolism; Methods; Molecular Profiling; Myocardial Infarction; Myocardial Revascularization; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Participant; Pathology; Pathway interactions; Predisposition; Procedures; Records; Renal Tissue; Renal function; Research; Research Personnel; Resources; Risk; Sampling; Seminal; Serum; Site; Stroke; Technology; Test Result; Testing; Time; Tissues; Transplant Recipients; Transplantation; Tubular formation; United States; Urine; Variant; adjudication; adverse outcome; base; biobank; clinical center; cohort; delayed graft function; exome sequencing; gene transplantation for gene therapy; genetic analysis; genetic variant; graft failure; high risk; improved; kidney allograft; kidney biopsy; living kidney donor; loss of function; metabolomics; multidisciplinary; programs; response; risk variant; transcriptome; transcriptome sequencing; urinary

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.

项目概要 非裔美国人 (AA) 中某些 APOL1 基因变异的发现表明，这些变异 是慢性肾脏病（CKD）发展的主要原因。事实上，某些 APOL1 基因变异 与欧洲相比，AA 地区终末期肾病 (ESRD) 的显着增加是主要原因 美国人（EA）。此外，具有这些相同 APOL1 基因变异的肾移植具有两倍的 增加失败。因此，了解这些 APOL1 基因如何促进肾移植非常重要 并找到可以增加或减少此类肾衰竭发生率的其他因素。还有 需要了解某些 APOL1 基因是否会影响活体 AA 肾捐赠者的健康。国家发展与发展委员会 APOLLO 网络是生成回答这些重要问题所需数据的关键一步。我们 在大西洋中部组建了一个由多个移植项目组成的网络，并组建了一个多学科团队 研究人员将聚集一大批 AA 肾脏捐赠者和接受者来跟踪他们的健康和肾脏状况 随着时间的推移发挥作用，并建立肾组织、血清和尿液生物库，为 有希望进行更多的未来研究。 某些 APOL1 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，例如 RNA 测序、外显子组 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，以帮助发现 APOL1 基因变异如何导致肾脏疾病。我们会将这些测试的结果与患者的健康状况联系起来 捐赠者和接受者及其肾脏的功能。 我们建议测试三个主要假设：1.) AA 中的某些 APOL1 基因变体可以激活 导致肾脏异常反应的途径，导致肾脏对 CKD 的易感性增加 捐助者； 2.) 在肾脏受者中，某些 APOL1 基因变异可以激活导致肾损伤的反应 CKD 和/或肾移植失败增加； 3.) 某些 APOL1 基因变异可以刺激 肾脏反应异常，导致捐赠者或接受者血压升高和心脏病。 为了检验这些假设，我们提出三个目标： 目标 1：(a) 建立一大群 AA 活肾 捐助者； (b) 建立血清和尿液生物库； (c) 检查 APOL1 基因与 肾脏疾病。目标 2：(a) 建立一大批 AA 肾接受者； (b) 进行肾活检， 血清和尿液生物样本库； (c) 确定 APOL1 基因与移植结果之间的关系； (四) 检查APOL1基因与肾活检病理学的关系； (e) 使用基于组学的 确定 APOL1 基因变异如何影响肾脏结果的方法。目标 3：(a) 评估关系 APOL1 基因变异与心脏病之间的关系。