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：
10599924
负责人：
PATRICIO E RAY
金额：
$ 36.34万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599924
关键词：
AIDS-Associated Nephropathy APOL1 gene Adult Affect African ancestry Autophagocytosis Autopsy Biopsy CRISPR/Cas technology Cell Line Cells Cessation of life Child Childhood Chronic Kidney Failure 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 Membrane Modeling Mononuclear Mus Names Nephrology Pathogenesis Pathway interactions Patients Persons Physiological Plasma Play Prevalence Process Risk Role Signal Pathway Structure TNF gene Technology Testing Transcript Tubular formation Tumor Necrosis Factor Receptor Urine Vacuole Viral Load result Workload antiretroviral therapy cytokine experimental study fly high risk in vivo inhibitor insight novel therapeutics particle podocyte prevent renal epithelium risk variant small hairpin RNA synergism tissue archive 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.

概括与HIV相关的肾病（Hivan）是由肾上皮细胞感染引起的肾脏疾病（REC）在携带两个Apol1风险等位基因（APOL1-RA）的非洲血统的人中，这种情况更频繁命名为G1或G2。 Hivan的研究提供了一个独特的机会来定义HIV+之间的联系方式炎性细胞和REC可能有助于建立肾脏HIV-1储层，并确定APOL1如何与HIV-1相互作用，在非洲血统的人群中促成Hivan。在赠款的第一个周期中，我们有证明跨膜TNF-α（TM-TNF-α）促进了足细胞的感染和REC培养来自Hivan的儿童，并增加与HIV-1协同作用中Apol1的表达。我们还发现 TM-TNF-α和APO1相互作用以调节与内吞作用，HIV-1运输和 rec中的降解。这是我们假设TM-TNF-α在儿童发病机理中起着至关重要的作用通过通过与单核细胞接触细胞对细胞接触的REC感染，Hivan以及增加这些细胞中Apol1-RA的活性。在艾滋病毒+足细胞中，这些变化使他们的体内平衡平衡，损害影响其结构，功能和生存的关键内吞和自噬途径。转弯，这些事件使儿童和成人造成了Hivan。该假设将以三个目标进行检验。在 AIM 1，我们将确定TM-TNF-α如何调节HIV-1从单核细胞转移到REC 从HIV+儿童培养，并阐明所涉及的机制。在AIM 2中，我们将定义TM-TNF-α如何 apol1-ra在体内相互作用，以调节相关的内吞和自噬途径，这对于果蝇肾细胞的正常功能（相当于人足细胞的蝇）和交通足细胞中的HIV-1颗粒。在AIM 3中，我们将确定APOL1-RA如何调节足细胞的感染由艾滋病毒+儿童培养，并定义了携带两个apol1 ra发展Hivan的风险。在摘要，这些实验将阐明REC被HIV-1感染的方式，并与肾脏浸润相互作用炎性细胞和Apol1-RA建立肾脏HIV-粘膜并诱导慢性肾脏疾病。