BFGF LOW AFFINITY RECEPTORS AND HIVAN

BFGF 低亲和力受体和 HIVAN

• 批准号: 6142444
• 负责人: PATRICIO E RAY
• 金额: $ 8.14万
• 依托单位: CHILDREN'S NATIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6142444
• 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.

在第一个资助期内，我们已经表明，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）发病机制中起着相关作用。本研究基于以下新结果：i）在患有HIVAN的儿童的血浆中发现高水平的bFGF; ii）bFGF增加HIV感染的外周血单核细胞（PBMC）与肾小管上皮细胞（RTEc）的粘附;iii）来自患有HIVAN的儿童的HIV-1分离物能够感染人RTEc）; iv）HIV感染的PBMC和RTEc表达新的bFGF结合蛋白（BP-FGF），其增强bFGF促有丝分裂和纤维化活性; v）将bFGF注射到HIV转基因小鼠（HIV-Tg）中加速肾病的进展。本申请的目的是检验以下假设：位于肾上皮细胞（REC）和肾细胞外基质上的硫酸乙酰肝素蛋白聚糖（HSPG）的数量增加促进bFGF和其它趋化因子的积累，增加HIV感染的PBMC的募集和诱导肾上皮损伤。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HIV-1原代分离株和对应于相同儿童的RTEc将用于检验bFGF诱导粘着斑接触形成并促进HIV-1转移至RTEc的假设。bFGF的作用将与RANTES和MIP-1 β进行比较研究，这两种趋化因子也与肾蛋白聚糖结合储存。2.定义一种新的bFGF结合蛋白（BP-FGF）如何由HIV感染的PBMC和RTEc产生调节bFGF活性和HIVAN的发病机制。我们希望确定HIV-1如何调节BP-FGF的表达、活性和释放;研究BP-FGF对培养的人RTEc的影响;并确定是否通过阻断BF-FGF活性，我们可以预防bFGF诱导的HIV-Tg小鼠HIVAN进展。3.确定gp 120调节bFGF活性和HIVAN发病机制的机制。将使用来自HIV感染儿童和HIV-Tg大鼠的RTEc进行研究，HIV-Tg大鼠是第一个显示与肾脏疾病相关的高水平循环gp 120的小动物模型。我们将定义gp 120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，可以应用于临床开发新的治疗方法，以防止艾滋病毒在儿童中的进展。