Basic FGF Low Affinity Receptors in HIVAN

描述（由申请人提供）：儿童hiv相关肾病（HIVAN）的特点是存在肾上皮增生性病变，引起局灶节段性肾小球硬化（FSGF）、肾小球塌陷和肾小管微囊性转化，导致大量蛋白尿、肾脏增大和快速慢性肾功能衰竭。非裔美国人对这种肾脏疾病表现出独特的易感性。在资助的最后阶段，我们发现HIV-Tat和肝素结合生长因子（HBGF）在肾脏中积累，与硫酸肝素蛋白聚糖（HSPG）结合，促进HIV-Tg小鼠hiv坍缩性肾小球病变的发展。我们还发现，hiv感染儿童尿液中HBGF的释放可以成为跟踪儿童hiv临床结果的有希望的生物标志物。根据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Gb3联合，增加HIV-1对肾上皮细胞（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在肾脏的积累。该假设的第二个推论是，这些变化诱导REc的持续生长、收缩性和通透性变化，并促进HIVAN患儿尿液中HBGF的释放。这些HBGF成为跟踪儿童hiv进展的可靠生物标志物。这一假设将在三个具体目标中得到验证：(1)确定HSPG和Gb3如何调节HIV-1附着、进入和/或融合到从hiv患儿身上采集的培养REc中；(2)确定病毒蛋白单独或联合HBGF如何调节HIVAN患儿尿液中培养的REc的生长、收缩和通透性行为。这些细胞将被筛选hiv基因组、HBGF、HSPG的存在，并进行基因分型，以表征MYH9基因的遗传变异，该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)确定我们实验室开发的一组新的尿液生物标志物和足细胞渗透性测定的临床价值，以跟踪儿童hiv的临床结果。我们相信，这些研究将产生基本的新知识，以提高我们对儿童艾滋病毒感染的发病机制的理解，并确定新的生物标志物，以跟踪艾滋病毒感染儿童的这种疾病的结果。

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.