Basic FGF Low Affinity Receptors in HIVAN

描述(申请人提供)：儿童HIV相关肾病(HIVAN)的特征是存在肾上皮细胞增生性病变，导致局灶性节段性肾小球硬化(FSGF)、肾小球塌陷和肾小管微囊化，导致大量蛋白尿、肾脏增大和快速慢性肾功能衰竭。非裔美国人表现出患这种肾脏疾病的独特易感性。在赠款的最后阶段，我们发现HIV-TAT和肝素结合生长因子(HBGF)在与硫酸乙酰肝素蛋白聚糖(HSPG)结合的肾脏中积累，加速了HIV-TG小鼠HIV塌陷性肾小球疾病的发展。我们还发现，HIV感染儿童尿液中HBGF的释放可以成为追踪儿童HIVAN临床结果的有前景的生物标志物。根据他人的数据和我们自己的初步数据，我们假设肾脏HSPG单独或与糖鞘糖脂Gb3结合，增加HIV-1与肾上皮细胞(Rec)的结合、附着和进入，导致慢性肾脏损伤和循环病毒蛋白和HBGF的肾脏积聚。这一假说的第二个推论是，这些变化导致Rec的持续生长、收缩和通透性变化，并促进HIVAN儿童尿中HBGF的释放。这些HBGF成为跟踪儿童HIVAN进展的可靠生物标记物。该假说将用于三个特定目标的验证：(1)确定HSPG和Gb3如何调控HIV-1与从HIVAN儿童的尿液收集的培养的Rc的附着、进入和/或融合；(2)确定病毒蛋白单独或与HBGF联合如何调节从HIVAN儿童的尿液收集的培养的Rc的生长、收缩和通透行为。这些细胞将被筛选出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塌陷性肾小球疾病有关。(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的临床结果。我们相信，这些研究将产生基本的新知识，以改善我们对儿童HIVAN发病机制的理解，并确定新的生物标记物来跟踪艾滋病毒感染儿童的这种疾病的结果。 公共卫生相关性：感染HIV-1的黑人儿童会患上一种名为HIV相关肾病(HIVAN)的致命肾脏疾病。几乎没有对感染艾滋病毒的儿童进行研究，以确定他们是如何患上肾脏疾病的。这项提议将填补与我们理解艾滋病毒-1如何单独或与循环病毒蛋白和肝素结合生长因子一起导致艾滋病毒感染儿童肾脏损伤的关键知识鸿沟。我们还将测试新的尿液生物标记物的作用，以确定患HIVAN的高危儿童，并使用他们的临床样本和HIV转基因小鼠跟踪HIV相关肾脏疾病的临床结果和治疗。

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.