BFGF LOW AFFINITY RECEPTORS AND HIVAN

BFGF 低亲和力受体和 HIVAN

• 批准号: 6177347
• 负责人: PATRICIO E RAY
• 金额: $ 27.77万
• 依托单位: CHILDREN'S NATIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177347
• 关键词: AIDS /HIV neuropathy; CD4 molecule; HIV envelope protein gp120; HIV infections; blood chemistry; cell adhesion; cell line; chemokine; child (0-11); fibroblast growth factor; fibronectins; gene expression; genetically modified animals; heparan sulfate; host organism interaction; human immunodeficiency virus 1; human subject; human tissue; integrins; kidney cell; laboratory mouse; lymphocyte; pathologic process; proteoglycan; ribozymes; tissue /cell culture; virus infection mechanism

During the first grant period we have shown that basic Fibroblast Growth Factor (bFGF) and its low affinity receptors play a relevant role in the pathogenesis of HIV-nephropathy (HIVAN) both in HIV-infected children and HIV-transgenic mice. This study is based on our following novel results: i) high levels of bFGF are found in the plasma of children with HIVAN; ii) bFGF increases the adhesion of HIV-infected peripheral blood mononuclear cells (PBMCs) to renal tubular epithelial cells (RTEc);iii) HIV-1 isolates derived from children with HIVAN are capable of infecting human RTEc); iv) HIV-infected PBMC's and RTEc express a novel bFGF- binding protein (BP-FGF) which potentiates bFGF mitogenic and fibrogenic activity; v) injection of bFGF into HIV-transgenic mice (HIV-Tg) accelerates the progression of renal disease. The goal of this application is to test the hypothesis that an increased number of heparan sulfate proteoglycans (HSPG) located on renal epithelial cells (REc) and the renal extracellular matrix facilitate the accumulation of bFGF and other chemokines, increasing the recruitment of HIV-infected PBMC's and the induction of renal epithelial injury. Three specific aims are proposed: 1. Determine the mechanisms by which bFGF and HSPG modulate the ability of HIV-1 to adhere, infect and/or injure REc. Cultured primary HIV-1 isolates and RTEc corresponding to the same children will e used to test the hypothesis that bFGF induces the formation of focal adhesion contacts and facilitates the transfer of HIV-1 to RTEc. The effects of bFGF will be studied in comparison with RANTES and MIP-1 beta, two chemokines which are also stored bound to renal proteoglycans. 2. Define how a novel bFGF binding protein (BP-FGF) produced by HIV-infected PBMC's and RTEc modulates bFGF activity and the pathogenesis of HIVAN. We expect to determine how HIV-1 regulates the expression, activity, and release of BP-FGF; investigate ow BP-FGF effects on cultured human RTEc; and define whether by blocking BF-FGF activity we could prevent bFGF-induced progression of HIVAN in HIV-Tg mice. 3. Determine the mechanisms by which gp120 modulates bFGF activity and the pathogenesis of HIVAN. Studies will be done using RTEc from HIV- infected children and HIV-Tg rats, the first small animal model showing high levels circulating gp120 in association with renal disease). We will define how gp120 modulates bFGF/HSPG activity and induces renal injury. All these studies will provide new knowledge that could be applied clinically to develop new treatments to prevent the progression of HIVAN in children.

在第一个资助期，我们已经证明碱性成纤维细胞生长因子（bFGF）及其低亲和力受体在hiv感染儿童和hiv转基因小鼠的hiv肾病（HIVAN）发病机制中发挥相关作用。本研究基于以下新结果：1)在hiv患儿血浆中发现高水平的bFGF；ii) bFGF增加hiv感染的外周血单个核细胞（PBMCs）对肾小管上皮细胞（RTEc）的粘附；iii)从感染艾滋病毒的儿童身上提取的HIV-1分离株能够感染人类RTEc)；iv) hiv感染的PBMC和RTEc表达一种新的bFGF结合蛋白（BP-FGF），增强bFGF有丝分裂和成纤维活性；v)向hiv转基因小鼠（HIV-Tg）注射bFGF加速肾脏疾病的进展。本应用的目的是验证位于肾上皮细胞（REc）和肾细胞外基质上的硫酸肝素蛋白聚糖（HSPG）数量的增加促进bFGF和其他趋化因子的积累，增加hiv感染的PBMC的募集和诱导肾上皮损伤的假设。提出了三个具体目标：1。确定bFGF和HSPG调节HIV-1粘附、感染和/或损伤REc的能力的机制。培养的原代HIV-1分离株和对应于同一儿童的RTEc将用于验证bFGF诱导局灶粘附接触的形成并促进HIV-1向RTEc转移的假设。将对bFGF的作用与RANTES和MIP-1 β进行比较，这两种趋化因子也与肾蛋白聚糖结合储存。2. 定义hiv感染的PBMC和RTEc产生的一种新的bFGF结合蛋白（BP-FGF）如何调节bFGF活性和hiv的发病机制。我们期望确定HIV-1如何调节BP-FGF的表达、活性和释放；探讨BP-FGF对培养人RTEc的影响；并确定阻断bfgf - fgf活性是否可以阻止bfgf诱导的HIV-Tg小鼠的hiv进展。3. 确定gp120调节bFGF活性的机制和HIVAN的发病机制。研究将使用来自HIV感染儿童和HIV- tg大鼠（第一个显示高水平循环gp120与肾脏疾病相关的小动物模型）的RTEc进行。我们将定义gp120如何调节bFGF/HSPG活性并诱导肾损伤。所有这些研究将提供新的知识，可用于临床开发新的治疗方法，以防止儿童艾滋病毒感染的进展。