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（由申请方提供）：尽管联合抗逆转录病毒治疗（cART）在控制HIV感染方面有效，但慢性进行性肾脏疾病（CKD）仍会导致HIV患者的显著发病率。艾滋病毒相关肾病（HIVAN）和局灶性节段性肾小球硬化症（FSGS）仍然是当代队列中患有慢性肾病的艾滋病毒患者活检中最常见的病理诊断。在美国，几乎90%的患有CKD的HIV感染受试者是非洲裔美国人。一项具有里程碑意义的发现将APOL 1基因的遗传变异与非裔美国人中晚期非糖尿病CKD的过度患病率相关联，已发表的隐性疾病模型的比值比为HIVAN为29，原发性FSGS为17。不仅APOL 1风险基因型独立加速CKD进展，具有APOL 1风险基因型和CKD的受试者不能从当前治疗中获益。虽然APOL 1肾病相关变异很常见（12%的非洲裔美国人携带风险基因型），但只有一部分人发展为晚期CKD，这与引发疾病的“二次打击”一致。我们先前的研究建立了直接HIV-1感染的要求， 肾细胞中HIVAN的发病机制，表明HIV是一种“二次打击”模式。“驱动APOL 1变异体与非裔美国人CKD相关的生物学机制尚不清楚。我们和其他小组发表的研究表明，肾细胞中表达的APOL 1介导疾病。由于APOL 1是人类和一些灵长类动物特有的基因，我们已经产生了小鼠模型，并从具有APOL 1风险基因型的受试者的尿液中培养足细胞，以发现和模拟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本的有限可用性，以测试以下假设：APOL 1在肾小球足细胞中具有抵抗环境应激和维持足细胞健康所必需的内源性功能，并且这些途径在两种风险变体存在下失调，其中临床疾病表现为引入环境应激。我们提出了两个具体的目标，以确定致病途径介导的APOL 1相关的肾脏疾病：目的1：使用比较基因组学，以确定候选途径介导的APOL 1相关的肾脏（足细胞）疾病。目标二：使用HIV-1感染作为模型触发器来表征介导APOL 1调节的防御对CKD诱导的足细胞的“第二次打击”的途径。虽然专注于APOL 1变异体-HIV相互作用，但这些因果途径可能识别与其他APOL 1相关CKD共享的机制。我们的团队非常适合进行这些研究，包括HIVAN发病机制，非裔美国人慢性肾脏疾病遗传学和最先进的基因组分析方面的专家。了解APOL 1变体与CKD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数据，推动非裔美国人CKD新诊断和治疗的发展。