Mechanisms of APOL1-mediated kidney disease

 描述(由申请人提供)：尽管联合抗逆转录病毒疗法(CART)在控制艾滋病毒感染方面有效，但慢性进行性肾病(CKD)会导致艾滋病毒患者的显著发病率。在当代队列中，HIV相关肾病(HIVAN)和局灶性节段性肾小球硬化(FSGS)仍然是CKD患者中最常见的病理诊断。在美国，几乎90%患有慢性肾脏病的艾滋病毒感染者是非裔美国人。一项里程碑式的发现将APOL1基因的遗传变异与晚期非糖尿病CKD在非裔美国人中的过度流行联系在一起，公布的隐性疾病模型在HIVAN和原发FSGS中的优势比为29和17。不仅APOL1风险基因型独立地加速了CKD的进展，APOL1风险基因型和CKD的受试者也不能从当前的治疗中受益。虽然与APOL1肾病相关的变异很常见(12%的非裔美国人携带风险基因)，但这些人中只有一小部分人发展为晚期CKD，这与引发疾病的“二次打击”一致。我们之前的研究确定了直接感染HIV-1的要求 肾细胞在HIVAN发病机制中的作用，表明HIV是一种典型的“二次打击”。驱动APOL1变异与非裔美国人慢性肾脏病关联的生物学机制尚不清楚。我们和其他研究小组发表的研究表明，在肾脏细胞中表达的APOL1参与了疾病的发生。由于APOL1是人类和一些灵长类动物独有的基因，我们建立了小鼠模型，并从APOL1风险基因携带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获得性，以检验以下假设：APOL1在肾小球足细胞中具有内源性功能，对于抵抗环境应激和维持足细胞健康是必要的，并且在存在两个风险变量的情况下，这些途径是失调的，其中临床疾病随着环境压力的引入而显现。我们提出了两个特定的目的来确定介导APOL1相关肾脏疾病的致病途径：目的1：利用比较基因组学来确定介导APOL1相关肾脏(足细胞)疾病的候选途径。目的2：用HIV-1感染作为模型触发器来表征介导APOL1调节的防御对CKD诱导的足细胞“二次打击”的途径。虽然专注于APOL1变体与HIV的相互作用，但这些因果途径可能确定与其他APOL1相关的CKD共享的机制。我们的团队是从事这些研究的理想人选，包括在HIVAN发病机制、非裔美国人慢性肾脏疾病的遗传学和最先进的基因组分析方面的知名专家。了解APOL1变异与CKD相关的机制是生物医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的新诊断和治疗方法的开发。

 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.