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

• 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
• 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

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：HIV 相关肾病 (HIVAN) 是一种肾脏疾病，几乎只见于非洲血统的人。它是由HIV-1感染和损伤足细胞和肾小管上皮细胞(RTEc)直接引起的。虽然体内HIV-1感染肾上皮细胞的机制尚未阐明，但内源性宿主因子被认为在此过程中发挥着至关重要的作用。此外，APOL1 基因 (G1/G2) 的变异最近被确定为成人患 HIVAN 的主要风险。确定 APOL1 变异促进 HIVAN 发展的机制可以深入了解 HIVAN 发病机制的潜在机制。最近，我们发现肿瘤坏死因子 α (TNF-a) 是促进 HIVAN 儿童培养的足细胞感染的关键宿主因子。在感染性 HIV-1 存在的情况下，TNF-a 还会增加 ApoL-1 的表达，ApoL-1 是一种在生理水平上调节自噬的蛋白质。我们假设 TNF-a 是宿主因子，通过促进肾上皮细胞感染和增加 ApoL-1 表达，在儿童 HIVAN 的发病机制中发挥关键作用。在 HIV-1 感染的足细胞中，APOL1 风险变异的过度表达会导致足细胞死亡增加，从而引发肾上皮损伤，从而促进 HIVAN 的发展。该假设将在三个目标上进行检验。在目标 1 中，我们将定义 TNF-a 如何影响病毒进入和 研究人员对 HIVAN 儿童培养的足细胞和 RTEc 进行感染，并鉴定了参与该过程的 TNF-a 结构域。在目标 2 中，我们将确定 ApoL-1 如何通过与 TNF-a、病毒蛋白以及病毒进入和降解的内吞或自噬途径相互作用来调节培养物中受感染足细胞的存活。在目标 3 中，我们将定义 APOL1 和 TNF-a 如何影响年轻野生型和 HIV-Tg26 小鼠的肾脏结果，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结果。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。