权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9884756
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884756
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 renal epithelium 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.

总结