Role of ctyokines and APOL-1 in the pathogenesis of childhood HIV associated neph

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：
8788974
负责人：
PATRICIO E RAY
金额：
$ 43万
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 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788974
关键词：
AIDS-Associated Nephropathy Adenovirus Vector Adult Affect African African American Autophagocytosis Blood Circulation Blood Pressure Cell Culture Techniques Cells Cessation of life Child Childhood Chronic Kidney Failure Clinical Co-Immunoprecipitations Collecting Cell Development Endocytosis Epithelial Epithelial Cells Equilibrium Focal Segmental Glomerulosclerosis Genes Genotype HIV HIV Envelope Protein gp120 HIV-1 Hypertension Infection Injury Integration Host Factors Kidney Kidney Diseases Knowledge Mass Spectrum Analysis Membrane Mus Names Outcome Pathogenesis Pathway interactions Phenotype Physiological Play Process Protein Array Proteins Proteinuria Relative (related person)Risk Risk Factors Role Sampling TNF gene Testing Transcript Tubular formation Tumor Necrosis Factor-alpha Urine Variant Viral Viral Proteins base cohort cytokine in vivo insight novel podocyte public health relevance receptor research study risk variant urinary

项目摘要

DESCRIPTION: HIV-associated nephropathy (HIVAN) is a renal disease almost exclusively seen in people of African ancestry. It is caused directly by the infection and injury of podocytes and renal tubular epithelial cells (RTEc) by HIV-1. While the mechanism for renal epithelial cell infection by HIV-1 in vivo has not been elucidated, endogenous host factors are believed to play a crucial role in this process. Additionally variants in the APOL1 gene (G1/G2) were recently identified as a major risk for developing HIVAN in adults. Identifying the mechanism by which APOL1 variants precipitate the development of HIVAN can provide insights into the underlying mechanism involved in the pathogenesis of HIVAN. Recently we identified tumor necrosis factor alpha (TNF-a) as a critical host factor that facilitates the infection of podocytes cultured from children with HIVAN. TNF-a, in presence of infectious HIV-1, also increases the expression of ApoL-1, a protein that at physiological levels regulates autophagy. We hypothesize that TNF-a is the host factor that plays a critical role in the pathogenesis of childhood HIVAN by facilitatin infection of renal epithelial cells and increasing ApoL-1expression. In HIV-1 infected podocytes, over expression of the APOL1 risk variants, tip the balance to increased podocyte death triggering renal epithelial injury, which precipitates in the development of HIVAN. This hypothesis will be tested in three aims. In aim 1, we will define how TNF-a affects viral entry and infection of podocytes and RTEc cultured from children with HIVAN, and identify the TNF-a domain involved in this process. In aim 2, we will determine how ApoL-1 modulates the survival of infected podocytes in culture by interacting with TNF-a, viral proteins, and endocytic or autophagic pathways for viral entry and degradation. In aim 3, we will define how APOL1 and TNF-a affect the renal outcome of young wild type and HIV-Tg26 mice, and validate relevant clinical findings in renal sections, cells, and urine samples collected from children with HIVAN. These experiments will generate highly relevant clinical information to understand how children develop HIVAN.

描述：与HIV相关的肾病（Hivan）是一种肾脏疾病，几乎完全在非洲血统中看到。它是由足细胞和肾小管上皮细胞（RTEC）直接引起的。尽管尚未阐明HIV-1肾上皮细胞感染的机制，但内源性宿主因子被认为在此过程中起着至关重要的作用。另外，最近将Apol1基因（G1/G2）中的变体视为成人发展Hivan的主要风险。确定Apol1变体沉淀Hivan的发展的机制可以提供对Hivan发病机理所涉及的潜在机制的见解。最近，我们确定肿瘤坏死因子α（TNF-A）是促进Hivan儿童培养的足细胞感染的关键宿主因子。在存在感染性HIV-1的情况下，TNF-A也增加了Apol-1的表达，Apol-1的表达是一种在生理水平上调节自噬的蛋白质。我们假设TNF-A是通过促进肾上皮细胞感染并增加Apol-1表达在儿童Hivan发病机理中起关键作用的宿主因子。在HIV-1感染的足细胞中，对Apol1风险变异的表达，将平衡倾斜至增加的足细胞死亡，从而触发肾上皮损伤，这会导致Hivan的发展。该假设将以三个目标进行检验。在AIM 1中，我们将定义TNF-A如何影响病毒进入和来自Hivan儿童培养的足细胞和RTEC的感染，并确定参与此过程的TNF-A领域。在AIM 2中，我们将通过与TNF-A，病毒蛋白以及内吞或自噬途径相互作用来确定APOL-1如何调节感染足细胞在培养中的存活。在AIM 3中，我们将定义APOL1和TNF-A如何影响年轻野生型和HIV-TG26小鼠的肾脏结局，并验证从Hivan儿童收集的肾脏切片，细胞和尿液样本中的相关临床发现。这些实验将产生高度相关的临床信息，以了解儿童如何发展Hivan。