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

 描述(申请人提供)：载脂蛋白L1(APOL1)的两个外显子遗传变异，在最近的非洲血统中很常见，对非裔美国人的肾脏健康有重大的负面影响。虽然APOL1与肾脏疾病的相关性已被反复证明，但APOL1相关性肾病的完整遗传结构及其潜在生物学尚不清楚。如果没有这样的知识，开发靶向药物疗法的能力是遥不可及的。长期目标是改善APOL1相关肾病患者的临床结果。这里的总体目标是通过整合来自肾病综合征研究网络登记的720名患有蛋白尿疾病的人类受试者的遗传、肾内转录、形态和临床数据，深入了解APOL1相关蛋白尿疾病的生物学。中心假设是高危的APOL1基因，以及APOL1表达的增加，会导致肾内基因表达的APOL1特异性和全基因组改变，肾脏的特殊形态变化，以及更差的临床结果。这一建议的基本原理是，更全面地了解APOL1的基因组生物学及其异常形式的肾内后果，可以导致基于分子的药理学策略的开发，以预防/治疗APOL1相关的蛋白尿症。这项研究的具体目标将是(1)发现与其肾小球和肾小管间质mRNA表达相关的APOL1基因座上的遗传因素，(2)确定与APOL1肾内mRNA表达相关的临床结果和生物学背景，以及(3)确定与APOL1相关蛋白尿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、RNA-Seq生成的基因表达谱的基因和转录本水平的特异性配对。Aim 2将分别将纵向建模和差异和相关基因表达方法应用于临床和全基因组转录数据。目标3将对超过650例活检的肾小球、肾小管间质和血管间隔进行深入的定量和定性的形态测量。这项研究的贡献在于从以人为本的肾内角度对APOL1相关性肾病的遗传结构和潜在的生物学机制有了更深入的了解。这一贡献将是重大的，因为它将产生关于APOL1相关肾病的洞察力，有可能直接转化为分子衍生的、有针对性的治疗策略。在我们看来，在这项申请中提出的研究是创新的，因为关于APOL1相关蛋白尿症的流行病学和生物学方面的发现将不仅直接来自一大批受影响的人类受试者，而且来自直接受到这些基因变异影响的肾脏组织。鉴于这种高危基因对肾脏疾病的普遍负面影响，这里的发现可能会扩大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。

 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.