APOL1-associated nephropathy from a human-derived, intrarenal perspective

从人源肾内角度看 APOL1 相关肾病

• 批准号: 9080860
• 负责人: MATTHEW Gordon SAMPSON
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9080860
• 关键词: AIDS-Associated Nephropathy; Address; Affect; African; African American; Alleles; American; Apolipoproteins; Architecture; Behavior; Biological; Biology; Biopsy; Blood Vessels; Chronic; Chronic Kidney Failure; Clinical; Data; Data Set; Development; Disease; End stage renal failure; Enrollment; Epidemiology; Etiology; European; Focal Segmental Glomerulosclerosis; Frequencies; Gene Expression; Genes; Genetic; Genome; Genotype; Goals; Health; Human; Individual; Injury; Intervention; Kidney; Kidney Diseases; Knowledge; Lead; Lupus Nephritis; Measurement; Mediating; Methods; Molecular Profiling; Morphology; Nephrotic Syndrome; Outcome; Pathologic; Patients; Pattern; Physical shape; Population; Quantitative Trait Loci; Race; Regulation; Renal glomerular disease; Research; Risk; Socioeconomic Status; Specificity; Targeted Research; Testing; Therapeutic; Tissues; Transcript; Translations; Undifferentiated; Variant; Work; base; blood pressure regulation; clinical phenotype; cohort; experience; functional decline; genetic variant; genome-wide; high risk; human subject; improved; innovation; insight; mRNA Expression; model building; novel; outcome forecast; prevent; prospective; public health relevance; risk variant; targeted treatment; transcriptome sequencing; transcriptomics

 DESCRIPTION (provided by applicant): Two exonic genetic variants in apolipoprotein L1 (APOL1), common in those of recent African ancestry, have a major negative impact on the kidney health of African-Americans. While its association with kidney disease has been reproducibly demonstrated, the full genetic architecture of APOL1 associated nephropathy, and its underlying biology, is unclear. Without such knowledge, the ability to develop targeted pharmacologic therapies is remote. The long-term goal is to improve clinical outcomes for individuals who have APOL1- associated nephropathy. The overall objective here is to gain a deep understanding of the biology of APOL1- associated proteinuric disease by integrating genetic, intrarenal transcriptomic, morphologic, and clinical datasets derived from 720 human subjects with proteinuric disease enrolled in the Nephrotic Syndrome Study Network. The central hypothesis is that the high-risk APOL1 genotype, as well as increased APOL1 expression, results in APOL1-specific and genome-wide alterations of intrarenal gene expression, specific morphologic changes in the kidney, and worse clinical outcomes. The rationale for this proposal is that a more complete understanding of the genome biology of APOL1, as well as the intrarenal consequences of its aberrant forms, can lead to development of molecularly-based pharmacologic strategies to prevent/treat APOL1-associated proteinuric disease. The specific aims of the study will be to (1) Discover genetic factors at the APOL1 locus associated with its glomerular and tubulointerstitial mRNA expression, (2) Determine the clinical outcomes and biologic context associated with intrarenal mRNA expression of APOL1, and (3) Define morphologic signatures associated with APOL1-associated proteinuric disease. Aim 1 will pair genotyping data with renal biopsy-based, RNA-Seq-generated gene expression profiles on the gene and transcript level of specificity. Aim 2 will apply longitudinal model building and differential- and intercorrelated-gene expression methods to clinical and genome-wide transcriptomic data, respectively. Aim 3 will use deep quantitative and qualitative morphologic measurements of the glomerular, tubulointerstitial, and vascular compartments of over 650 biopsies. The contribution here is expected to be an increased understanding of the genetic architecture and potential biological mechanisms underlying APOL1-associated nephropathy, from a human-based, intrarenal perspective. This contribution will be significant because it will produce insights about APOL1- associated nephropathy with potential for direct translation into molecularly-derived, targeted therapeutic strategies. The research proposed in this application is innovative, in our opinion, because the discoveries made regarding the epidemiology and biology of APOL1-associated proteinuric disease will be directly derived not only from a large cohort of affected human subjects, but from the kidney tissue directly impacted by these genetic variants. Given the high-risk genotype's generalized negative impact across kidney conditions, discoveries made here may be extended to improve the health of a larger group of African-Americans beyond those with proteinuric disease.

 描述（由申请人提供）：载脂蛋白L1（APOL 1）中的两种外显子遗传变异，在最近的非洲血统中很常见，对非洲裔美国人的肾脏健康有重大的负面影响。虽然其与肾脏疾病的关联已被反复证实，但APOL 1相关肾病的完整遗传结构及其基础生物学尚不清楚。没有这些知识，开发靶向药物治疗的能力是遥远的。长期目标是改善APOL 1相关肾病患者的临床结局。本文的总体目标是通过整合来自肾病综合征研究网络中720名患有蛋白尿疾病的人类受试者的遗传、肾内转录组、形态学和临床数据集，深入了解APOL 1相关蛋白尿疾病的生物学。中心假设是高风险APOL 1基因型以及APOL 1表达增加导致肾内基因表达的APOL 1特异性和全基因组改变、肾脏的特异性形态学改变和更差的临床结局。该提议的基本原理是，对APOL 1基因组生物学及其异常形式的肾内后果的更完整理解，可以导致开发基于分子的药理学策略来预防/治疗APOL 1相关蛋白尿疾病。本研究的具体目的是（1）发现与肾小球和肾小管间质mRNA表达相关的APOL 1基因座遗传因素，（2）确定与肾内APOL 1 mRNA表达相关的临床结局和生物学背景，以及（3）定义与APOL 1相关蛋白尿疾病相关的形态学特征。目的1将基因分型数据与基于肾活检的RNA-Seq生成的基因表达谱在基因和转录水平上的特异性配对。目标2将应用纵向模型的建立和差异和相互关联的基因表达的方法，临床和全基因组转录组数据，分别。目标3将使用超过650个活检组织的肾小球、肾小管间质和血管室的深层定量和定性形态学测量。本文的贡献有望从人类肾内角度加深对APOL 1相关肾病的遗传结构和潜在生物学机制的理解。这一贡献将是重要的，因为它将产生关于APOL 1相关肾病的见解，并有可能直接转化为分子衍生的靶向治疗策略。在我们看来，本申请中提出的研究是创新的，因为关于APOL 1相关蛋白尿疾病的流行病学和生物学的发现不仅直接来自于大量受影响的人类受试者，而且直接来自于受这些遗传变异影响的肾脏组织。鉴于高风险基因型对肾脏疾病的普遍负面影响，这里的发现可能会扩展到改善更多非裔美国人的健康，而不仅仅是那些患有蛋白尿疾病的人。