Basic FGF Low Affinity Receptors in HIVAN

HIVAN 中的基本 FGF 低亲和力受体

• 批准号: 8201890
• 负责人: PATRICIO E RAY
• 金额: $ 4.05万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201890
• 关键词: AIDS-Associated Nephropathy; Adult; Affinity; African American; Behavior; Binding; Biological Assay; Biological Markers; Cells; Child; Childhood; Chronic; Chronic Kidney Failure; Clinic; Clinical; Data; Development; Disease Outcome; Epithelial; Epithelial Cells; Epithelium; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Focal Segmental Glomerulosclerosis; Genes; Genetic Variation; Genome; Genotype; Glycosphingolipids; Grant; Growth; HIV; HIV Envelope Protein gp120; HIV-1; Harvest; Heparan Sulfate Proteoglycan; Heparin Binding Growth Factor; Heparitin Sulfate; In Vitro; Injury; Kidney; Kidney Diseases; Knowledge; Laboratories; Lesion; Membrane Microdomains; Methods; Monitor; Mus; Names; Nonmuscle Myosin Type IIA; Outcome; Pathogenesis; Patients; Permeability; Predisposition; Proteinuria; Renal tubule structure; Role; Sampling; Structure; Testing; Transgenic Mice; Treatment outcome; Tubular formation; Urine; Vascular Endothelial Growth Factors; Viral Proteins; base; globotriaosylceramide; gp-120 Antigen; high risk; improved; in vivo; kidney cell; non-muscle myosin; novel; podocyte; public health relevance; receptor; research study; response; urinary

DESCRIPTION (provided by applicant): Childhood HIV-associated nephropathy (HIVAN) is characterized by the presence of renal epithelial proliferative lesions that cause focal segmental glomerulosclerosis (FSGF), glomerular collapse, and microcystic transformation of renal tubules leading to heavy proteinuria, renal enlargement, and rapid chronic renal failure. African Americans show a unique susceptibility to develop this renal disease. During the last period of the grant we found that HIV-Tat and heparin binding growth factors (HBGF) accumulated in the kidney bound to heparan sulfate proteglycans (HSPG) precipitate the development of HIV-collapsing glomerulopathy in HIV-Tg mice. We also found that HBGF release in the urine of HIV-infected children can become promising biomarkers to follow the clinical outcome of childhood HIVAN. Based on data generated by others and our own preliminary data, we hypothesize that renal HSPG, alone or in combination with the glycosphingolipid Gb3, increase the binding, attachment, and entry of HIV-1 to renal epithelial cells (REc), causing chronic renal injury and renal accumulation of circulating viral proteins and HBGF. A second corollary of this hypothesis, is that these changes induce persistent growth, contractility, and permeabiliy changes in REc, and facilitate the release of HBGF in the urine of children with HIVAN. These HBGF become then reliable biomarkers to follow the progression of HIVAN in children. This hypothesis will be tested in threee specific aims: (1) To define how HSPG and Gb3 modulate the attachment, entry and or fusion of HIV-1 to cultured REc harvested from children with HIVAN; (2) To determine how viral proteins, alone or in combination with HBGF, modulate the growth, contractilty, and permeability behaviors of cultured REc harvested from the urine of children with HIVAN. These cells will be screened for the presence of the HIV-genome, HBGF, HSPG, and genotyped to characterize a genetic variation in the MYH9 gene, encoding the non-muscle myosin IIA heavy chain, that is associated with HIV-collapsing glomerulopathy in adults. (3) To determine the clinical value of a new panel of urinary biomarkers, and a podocyte-permeability assay developed in our lab, to follow the clinic outcome of childhood HIVAN. We are confident that these studies will generate fundamental new knowledge to improve our understanding of the pathogenesis of childhood HIVAN and identify new biomarkers to follow the outcome of this disease in HIV-infected children. PUBLIC HEALTH RELEVANCE: Black children infected with HIV-1 can develop a lethal renal disease named HIV- associated nephropathy (HIVAN). Very few studies have been done in HIV-infected children to determine how they develop renal disease. This proposal will close a critical knowledge gap related to our understanding of how HIV-1, alone or in combination with circulating viral proteins and heparin binding growth factors, causes kidney injury in HIV-infected children. We will also test the role of new urinary biomarkers to identify children at high risk of developing HIVAN, and to follow the clinical outcome and treatment of HIV-associated renal diseses using their clincial samples and HIV-transgenic mice.

描述（由申请人提供）：儿童期HIV相关肾病（HIVAN）的特征为存在肾上皮增生性病变，可引起局灶节段性肾小球硬化（FSGF）、肾小球塌陷和肾小管微囊变，导致大量蛋白尿、肾肿大和快速慢性肾衰竭。非裔美国人表现出独特的易感性，发展这种肾脏疾病。在资助的最后一段时间，我们发现HIV-Tat和肝素结合生长因子（HBGF）在肾脏中积累，与硫酸乙酰肝素蛋白聚糖（HSPG）结合，促使HIV-Tg小鼠发生HIV塌陷性肾小球病。我们还发现，HIV感染儿童尿液中HBGF的释放可以成为有希望的生物标志物，以跟踪儿童HIVAN的临床结果。基于其他人的数据和我们自己的初步数据，我们假设肾脏HSPG单独或与鞘糖脂Gb 3联合使用，增加了HIV-1与肾上皮细胞（REC）的结合、附着和进入，导致慢性肾损伤和循环病毒蛋白和HBGF在肾内蓄积。该假设的第二个推论是，这些变化诱导REC的持续生长、收缩性和渗透性变化，并促进HIVAN儿童尿液中HBGF的释放。这些HBGF随后成为追踪儿童HIVAN进展的可靠生物标志物。这一假设将在三个特定的目标进行测试：（1）确定HSPG和Gb 3如何调节HIV-1与从HIVAN儿童收集的培养的REC的附着、进入和/或融合;（2）确定病毒蛋白，单独或与HBGF组合，如何调节从HIVAN儿童尿液收集的培养的REC的生长、收缩和渗透行为。将对这些细胞进行HIV基因组、HBGF、HSPG筛查，并进行基因分型，以表征MYH 9基因中的遗传变异，MYH 9基因编码非肌肉肌球蛋白IIA重链，与成人HIV塌陷性肾小球病相关。(3)确定一组新的尿液生物标志物和我们实验室开发的足细胞通透性测定的临床价值，以跟踪儿童HIVAN的临床结局。我们相信，这些研究将产生基本的新知识，以提高我们对儿童HIVAN发病机制的理解，并确定新的生物标志物，以跟踪这种疾病在HIV感染儿童中的结果。 公共卫生相关性：感染HIV-1的黑人儿童可能会发展成一种致命的肾脏疾病，称为HIV相关性肾病（HIVAN）。很少有研究已经在艾滋病毒感染的儿童，以确定他们如何发展肾脏疾病。这项提案将填补一个关键的知识空白，这与我们对HIV-1如何单独或与循环病毒蛋白和肝素结合生长因子结合导致HIV感染儿童肾损伤的理解有关。我们还将测试新的尿液生物标志物的作用，以确定儿童在发展艾滋病毒的高风险，并遵循临床结果和治疗艾滋病毒相关的肾脏疾病使用他们的临床样本和艾滋病毒转基因小鼠。