Basic FGF Low Affinity Receptors in HIVAN

HIVAN 中的基本 FGF 低亲和力受体

• 批准号: 7931677
• 负责人: PATRICIO E RAY
• 金额: $ 25.8万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931677
• 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 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.

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.非裔美国人表现出一种独特的发展这种肾脏疾病的敏感性。在赠款的最后一个时期，我们发现HIV-TAT和肝素结合生长因子（HBGF）积聚在与硫酸乙酰肝素proteglycans（HSPG）结合的肾脏中，这会导致HIV-TG小鼠中HIV胶囊肾小球疾病的发展。我们还发现，在感染HIV的儿童尿液中的HBGF释放可能会成为有前途的生物标志物，遵循儿童Hivan的临床结果。基于他人产生的数据和我们自己的初步数据，我们假设肾脏HSPG单独或与糖磷脂胆脂GB3相结合，增加了HIV-1对肾上皮细胞（REC）的结合，依恋和进入，从而导致慢性肾脏损伤和导致循环病毒蛋白和HBGF的肾脏积累。该假设的第二个推论是，这些变化会导致REC的持续增长，收缩力和通透性变化，并促进HBGF在Hivan儿童尿液中释放。这些HBGF随后成为可靠的生物标志物，跟随儿童的Hivan进展。该假设将在特定的目的中进行检验：（1）定义HSPG和GB3如何调节HIV-1与HIVS的培养养殖的附着，进入和或融合。 （2）确定病毒蛋白如何单独或与HBGF结合使用，调节从Hivan儿童尿液中收获的培养的Rec的生长，合同和渗透率行为。这些细胞将被筛选为HIV基因组，HBGF，HSPG的存在和基因分型，以表征MYH9基因的遗传变异，编码非肌肉肌球蛋白IIA重链，这与成人HIV相处的肾小球病有关。 （3）确定新的泌尿生物标志物小组的临床价值以及我们实验室中开发的足细胞 - 透露率测定法，以遵循儿童Hivan的临床结果。我们有信心这些研究将产生基本的新知识，以提高我们对童年hivan的发病机理的理解，并确定新的生物标志物以遵循感染HIV感染的儿童的结果。 公共卫生相关性：感染HIV-1的黑人儿童可以发展出一种致命的肾脏疾病，称为HIV-相关肾病（Hivan）。在感染HIV的儿童中，很少有研究来确定他们如何发展肾脏疾病。该提案将缩小与我们对HIV-1单独或与循环病毒蛋白和肝素结合生长因子的理解有关的关键知识差距，这会导致HIV感染的儿童肾脏损伤。我们还将测试新的泌尿生物标志物在鉴定出患有HIVAN的高风险的儿童，并使用其clincial样品和HIV转基因小鼠遵循与HIV相关的肾脏疾病的临床结果和治疗。