Mechanisms of APOL1-mediated kidney disease

APOL1 介导的肾脏疾病的机制

• 批准号: 9319750
• 负责人: Leslie A Bruggeman
• 金额: $ 5.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-21 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319750
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; African American; Aging; Alpha Cell; Anti-Retroviral Agents; Antiviral Response; Automobile Driving; Biological; Biopsy; Cell model; Chronic; Chronic Kidney Failure; Clinical; Complication; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disease model; Focal Segmental Glomerulosclerosis; Genes; Genetic; Genetic Variation; Genetic study; Genomics; Genotype; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-1; Health; Human; In Vitro; Individual; Infection; Kidney; Kidney Cell Infection; Kidney Diseases; Link; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Odds Ratio; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Pathway interactions; Patients; Population; Positioning Attribute; Prevalence; Primates; Process; Publishing; Role; Sampling; Science; Stress; Testing; Transcend; Transcript; Transgenes; Transgenic Mice; Urine; Variant; Virus; base; clinically relevant; cohort; comparative genomics; differential expression; in vivo; kidney cell; mouse model; non-diabetic; novel diagnostics; novel therapeutics; podocyte; public health relevance; risk variant; therapy design; tool; transcriptome; urinary

 DESCRIPTION (provided by applicant): Despite the efficacy of combined anti-retroviral therapy (cART) in control of HIV infection, chronic, progressive kidney disease (CKD) causes significant morbidity in HIV patients. HIV-associated nephropathy (HIVAN) and focal segmental glomerulosclerosis (FSGS) remain the most prevalent pathological diagnoses in biopsies from HIV patients with CKD in contemporary cohorts. In the U.S., almost 90% of HIV infected subjects with CKD are African American. A landmark discovery associated genetic variation in the APOL1 gene with excess prevalence of advanced, non-diabetic CKD in African Americans, with published odds ratios for a recessive model of disease of 29 for HIVAN and 17 for primary FSGS. Not only do APOL1 risk genotypes independently accelerate CKD progression, subjects with APOL1 risk genotype and CKD do not benefit from current treatment. Although APOL1 kidney disease-associated variants are common (12% of African Americans carry the risk genotype), only a subset of these individuals develop advanced CKD, consistent with a "second hit" to initiate disease. Our prior studies established a requirement for direct HIV-1 infection of kidney cells in HIVAN pathogenesis, indicating HIV is a model "second hit." The biological mechanisms driving the association of APOL1 variants with CKD in African Americans are unknown. Studies published by us and other groups suggest APOL1 expressed in kidney cells mediates disease. Since APOL1 is a gene unique to humans and some primates, we have generated mouse models and cultured podocytes from urine of subjects with APOL1 risk genotypes to discover and model the mechanisms by which HIV-1 infection triggers CKD in susceptible individuals. These tools overcome the limited availability of human samples to test the following hypothesis: APOL1 has an endogenous function in the glomerular podocyte that is necessary to resist environmental stress and maintain podocyte health and these pathways are dysregulated in the presence of two risk variants where clinical disease manifests with the introduction of an environmental stress. We propose two specific aims to identify pathogenic pathways the mediate APOL1-associated kidney diseases: Aim 1: Use comparative genomics to identify candidate pathways mediating APOL1-associated kidney (podocyte) diseases. Aim 2: Use HIV-1 infection as a model trigger to characterize pathways mediating APOL1 regulated defenses to a CKD-inducing "second hit" to the podocyte. While focused on the APOL1 variant-HIV interactions, these causal pathways may identify mechanisms shared with other APOL1-associated CKDs. Our group is ideally positioned to undertake these studies, including established experts in HIVAN pathogenesis, genetics of chronic kidney disease in African Americans, and state-of-the-art genomic analysis. Understanding the mechanisms by which variant APOL1 associates with CKD is one of the most compelling questions in biomedical science, and these studies could potentially produce data that drives development of novel diagnostics and treatments for CKD in African Americans.

 描述（由适用提供）：尽管抗逆转录病毒疗法（CART）在控制HIV感染，慢性，进行性肾脏疾病（CKD）方面具有有效性，导致HIV患者的发病率很高。与HIV相关的肾病（Hivan）和局灶性节段性肾小球硬化症（FSGS）仍然是当代同胞中CKD患者的活检中最普遍的患者诊断。在美国，近90％的艾滋病毒感染受试者是非裔美国人。具有里程碑意义的发现与APOL1基因中的遗传变异有关，非洲裔美国人的晚期非糖尿病性CKD的患病率超过了Hivan疾病的隐性疾病模型，而初级FSG的疾病模型为29个疾病模型。 APOL1风险基因型不仅独立加速了CKD进展，具有APOL1风险基因型和CKD的受试者不会受益于当前治疗。尽管APOL1肾脏疾病相关的变异很常见（非洲裔美国人占风险基因型的12％），但这些人中只有一部分会发展出晚期CKD，这与启动疾病的“第二次命中”一致。我们先前的研究确定了直接HIV-1感染的要求 Hivan发病机理中的肾细胞，表明HIV是模型“第二击”。在非洲裔美国人中，推动APOL1变体与CKD的关联的生物学机制尚不清楚。美国和其他小组发表的研究表明，在肾细胞中表达的APOL1介导疾病。由于APOL1是人类和某些私有物质独有的基因，因此我们从患有APOL1风险基因型的受试者的尿液中产生了小鼠模型和培养的足细胞，以发现和建模HIV-1感染在易感个体中触发CKD的机制。这些工具克服了人类样品可用性以测试以下假设的有限可用性：APOL1在肾小球足细胞中具有内源性功能，这对于抵制环境压力和维持足细胞健康是必要的，并且在存在两个风险变化的情况下，这些途径在临床疾病的存在下伴随着环境压力的引入。我们提出了两个特定的目的，以识别介导APOL1相关的肾脏疾病的致病途径：AIM 1：使用比较基因组学识别介导APOL1相关肾脏（Podocyte）疾病的候选途径。 AIM 2：使用HIV-1感染作为模型触发，以表征介导APOL1调节防御的途径，以诱导CKD的“第二击”到足细胞。尽管专注于APOL1变体HIV相互作用，但这些灾难性途径可能会识别与其他与APOL1相关的CKD共享的机制。理想地有能力进行这些研究，其中包括Hivan发病机理的知名专家，非洲裔美国人的慢性肾脏疾病遗传学以及最先进的基因组分析。了解与CKD相关的变体APOL1相关的机制是生物医学科学中最引人注目的问题之一，这些研究可能会产生可推动非裔美国人CKD新颖诊断和治疗方法发展的数据。