Basic FGF Low Affinity Receptors in HIVAN

描述（由申请人提供）：儿童 HIV 相关肾病 (HIVAN) 的特征是存在肾上皮增殖性病变，导致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、肾肿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，与硫酸乙酰肝素蛋白聚糖 (HSPG) 结合，促进 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 的释放可以成为追踪儿童 HIVAN 临床结果的有前景的生物标志物。根据其他人产生的数据和我们自己的初步数据，我们假设肾 HSPG 单独或与糖鞘脂 Gb3 组合，会增加 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 的肾积聚。该假说的第二个推论是，这些变化引起 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。这一假设将在三个具体目标上进行检验：(1) 确定 HSPG 和 Gb3 如何调节 HIV-1 与从 HIVAN 儿童身上采集的培养 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 儿童尿液中收集的培养 REc 的生长、收缩性和通透性行为。这些细胞将被筛选是否存在 HIV 基因组、HBGF、HSPG，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 HIVAN 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 HIVAN 发病机制的理解，并确定新的生物标志物来跟踪 HIV 感染儿童的这种疾病的结果。 公共卫生相关性：感染 HIV-1 的黑人儿童可能会患上一种致命的肾脏疾病，称为 HIV 相关肾病 (HIVAN)。对于感染艾滋病毒的儿童进行的研究很少，以确定他们如何患上肾脏疾病。该提案将弥补我们对 HIV-1（单独或与循环病毒蛋白和肝素结合生长因子结合）如何导致 HIV 感染儿童肾损伤的理解相关的关键知识差距。我们还将测试新的尿液生物标志物的作用，以识别罹患 HIVAN 的高风险儿童，并使用其临床样本和 HIV 转基因小鼠跟踪 HIV 相关肾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.