Role of cytokines and APOL-1 in the pathogenesis of childhood HIV associated nephrology

细胞因子和 APOL-1 在儿童 HIV 相关肾病发病机制中的作用

基本信息

批准号：
9790493
负责人：
PATRICIO E RAY
金额：
--
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-04-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9790493
关键词：
AIDS-Associated Nephropathy APOL1 gene Adult Affect African Archives Autophagocytosis Autopsy Biopsy CRISPR/Cas technology Cell Line Cells Cessation of life Child Childhood Chronic Kidney Failure Cultured Cells Development Drosophila genus Dynamin Endocytosis Epithelial Cells Equilibrium Event Genes Genotype Grant HIV HIV Infections HIV-1 Human Impairment Infection Inflammatory Inflammatory Infiltrate Kidney Kidney Diseases Kidney Transplantation Knowledge Lead Modeling Mononuclear Mus Names Nephrology Pathogenesis Pathway interactions Patients Physiological Plasma Play Prevalence Process Risk Role Signal Pathway Structure TNF gene Technology Testing Tissues Transcript Tubular formation Tumor Necrosis Factor Receptor Urine Vacuole Viral Load result Workload antiretroviral therapy cytokine experimental study fly high risk in vivo inhibitor/antagonist insight novel therapeutics particle podocyte prevent risk variant small hairpin RNA synergism trafficking transmission process young adult

项目摘要

SUMMARY HIV-associated nephropathy (HIVAN) is a renal disease caused by the infection of renal epithelial cells (REc) that is seen more frequently in people of African ancestry who carry two APOL1 risk alleles (APOL1-RA) named G1 or G2. The study of HIVAN provides a unique opportunity to define how contacts between HIV+ inflammatory cells and REc may contribute to establish a kidney HIV-1 reservoir, and to determine how APOL1 interact with HIV-1 to precipitate HIVAN in people of African ancestry. In the first cycle of the grant, we have demonstrated that transmembrane TNF-α (tm-TNF-α) facilitates the infection of podocytes and REc cultured from children with HIVAN, and increases the expression of APOL1 in synergy with HIV-1. We also found that tm-TNF-α and APO1 interact to modulate common pathways involved in endocytosis, HIV-1 trafficking, and degradation in REc. Thus, we hypothesize that tm-TNF-α plays a critical role in the pathogenesis of childhood HIVAN by facilitating the infection of REc through cell-to-cell contacts with mononuclear cells, and by increasing the activity of APOL1-RA in these cells. In HIV+ podocytes, these changes tip their homeostatic balance, impairing key endocytic and autophagic pathways that affect their structure, function, and survival. In turn, these events precipitate HIVAN in children and adults. This hypothesis will be tested in three aims. In aim 1, we will determine how tm-TNF-α modulates the transfer of HIV-1 from mononuclear cells to REc cultured from HIV+ children, and elucidate the mechanisms involved. In aim 2 we will define how tm-TNF−α and APOL1-RA interact in vivo to modulate relevant endocytic and autophagy pathways that are essential for the normal function of Drosophila nephrocytes (the fly equivalent of human podocytes) and for the traffic of HIV-1 particles in podocytes. In aim 3, we will determine how APOL1-RA modulate the infection of podocytes cultured from HIV+ children, and define the risk of children carrying two APOL1 RA to develop HIVAN. In summary, these experiments will elucidate how REc are infected with HIV-1, and interact with renal infiltrating inflammatory cells and the APOL1-RA to establish a renal HIV-reservoir and induce chronic kidney diseases.

概括 HIV相关肾病（HIVAN）是一种由肾上皮细胞（REc）感染引起的肾脏疾病这种情况在携带两个 APOL1 风险等位基因 (APOL1-RA) 的非洲血统人群中更为常见 HIVAN 的研究提供了一个独特的机会来定义 HIV+ 之间的接触方式。炎症细胞和 REc 可能有助于建立肾脏 HIV-1 储存库，并确定 APOL1 如何作用与 HIV-1 相互作用，在非洲血统的人体内促进 HIVAN 在第一个资助周期中，我们已经完成了这项工作。证明跨膜 TNF-α (tm-TNF-α) 促进足细胞和培养的 REc 的感染我们还发现，APOL1 的表达与 HIV-1 协同作用。 tm-TNF-α 和 APO1 相互作用，调节参与胞吞作用、HIV-1 运输和因此，我们认为 tm-TNF-α 在儿童发病机制中发挥着关键作用。 HIVAN 通过与单核细胞的细胞间接触促进 REc 的感染，并通过在 HIV+ 足细胞中，增加 APOL1-RA 的活性，这些变化会改变它们的稳态。平衡，损害影响其结构、功能和生存的关键内吞和自噬途径。反过来，这些事件会导致儿童和成人感染 HIV。这一假设将在三个方面得到检验。目标 1，我们将确定 tm-TNF-α 如何调节 HIV-1 从单核细胞到 REc 的转移从 HIV+ 儿童中培养，并阐明其相关机制。在目标 2 中，我们将定义 tm-TNF−α。和 APOL1-RA 在体内相互作用，调节相关的内吞和自噬途径，这对于果蝇肾细胞（果蝇相当于人类足细胞）的正常功能以及足细胞中的 HIV-1 颗粒在目标 3 中，我们将确定 APOL1-RA 如何调节足细胞的感染。从 HIV+ 儿童中培养，并确定携带两种 APOL1 RA 的儿童患 HIVAN 的风险。总之，这些实验将阐明 REc 如何感染 HIV-1，并与肾浸润相互作用炎症细胞和 APOL1-RA 建立肾脏 HIV 储存库并诱发慢性肾脏疾病。