BFGF LOW AFFINITY RECEPTORS AND HIVAN

BFGF 低亲和力受体和 HIVAN

• 批准号: 6142442
• 负责人: PATRICIO E RAY
• 金额: $ 1.09万
• 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: 1999-07-15 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6142442
• 关键词: BFGF; LOW; AFFINITY; RECEPTORS; HIVAN

The long-term goal of our study is to clarify the pathogenesis of the proliferative lesions in HIV-1 associated nephropathy (HIVAN). Based on previous work done by others and our preliminary data using an HIV-1 transgenic murine model of HIVAN, we hypothesize that the proliferative changes present in HIVAN are partially related to alterations in bFGF released by injured cells. The strong binding affinity of bFGF to heparin, suggest that bFGF released by injured cells could be bound to renal heparin-like molecules such as heparan sulfate proteoglycans (HSPG) located on the cell surface or extracellular matrix. HSPG may affect bFGF interaction with its high affinity receptors potentiating its mitogenic effects. Thus, renal HSPG could play a dual role in HIVAN: 1) increasing virus adsorption and possible infection of renal cells, and 2) inducing proliferation by facilitating bFGF storage in renal tissue. The specific aims of this study are: 1. Determine whether HSPG located on renal proximal tubular epithelial cells (RPTEc) interact with HIV envelope protein gp120 facilitating virus binding and entry. a) Characterize the proteoglycan content of human RPTEc. b) Define binding interactions between gp120 and HSPG on the cell surface of RPTEc. c) Determine whether RPTEc could be infected by macrophage-tropic or T cell tropic HIV-1 viruses, and evaluate the role of HSPG on this process. We expect to define the role of HSPG on HIV-1 virus attachment and entry to RPTEc. 2. Define whether HIV-1 viral products influence bFGF activity and cell growth. a) Identify renal cell types producing, releasing, and responding to bFGF mitogenic effects. b) Evaluate the role of HIV-1 viral products tat and gp120 on renal growth, bFGF synthesis and release. c) Define whether proteolytic enzymes induced by HIV infection, may facilitate bFGF release from renal cells and extracellular matrix. We expect to determine how HIV-1 viral products influence bFGF activity and cell growth in renal tissue. 3. Determine the role of bFGF and its receptors in the pathogenesis of HIVAN in HIV transgenic mice. a) Define topographical distribution and number of bFGF low and high affinity binding sites in control and transgenic kidneys. b) Identify novel bFGF binding proteins in transgenic RTEc. c) Determine renal gene expression of bFGF high affinity receptors (FGFR-1, FGFR-2). d) Define in vivo effects of bFGF on renal growth and HIV expression. e) Evaluate therapies to block bFGF low affinity receptors or bFGF gene expression in renal tissue. We expect these experiments to define the interrelationships between bFGF accumulation in renal tissue and kidney growth, and to test potential therapies to prevent the progression of HIVAN.

我们这项研究的长期目标是阐明 HIV-1相关肾病(HIVAN)的增生性病变。基于 其他人之前所做的工作和我们使用HIV-1病毒的初步数据 转基因HIVAN小鼠模型的建立，我们假设 HIVAN中存在的变化部分与bFGF的变化有关 由受损细胞释放。碱性成纤维细胞生长因子与碱性成纤维细胞生长因子 肝素，提示损伤细胞释放的bFGF可能与 肾脏类肝素分子，如硫酸乙酰肝素蛋白多糖(HSPG) 位于细胞表面或细胞外基质上。HSPG可能影响碱性成纤维细胞生长因子 与其高亲和力受体的相互作用增强其有丝分裂 效果。因此，肾脏HSPG在HIVAN中可能起双重作用：1)增加 病毒吸附和可能的肾细胞感染；2)诱导 通过促进碱性成纤维细胞生长因子在肾组织中的储存促进细胞增殖。具体的 本研究的目的是：1.确定HSPG是否位于肾脏 近端肾小管上皮细胞(RPTEc)与HIV包膜相互作用 蛋白gp120促进病毒结合和进入。A)描述 人RPTEc的蛋白多糖含量。B)定义绑定相互作用 在RPTEc细胞表面的gp120和HSPG之间。C)确定是否 RPTEc可被嗜巨噬细胞或嗜T细胞的HIV-1感染 病毒，并评估HSPG在这一过程中的作用。我们希望 确定HSPG在HIV-1病毒附着和进入RPTEc中的作用。2. 确定HIV-1病毒产品是否影响碱性成纤维细胞生长因子活性和细胞 成长。A)确定产生、释放和反应的肾细胞类型 碱性成纤维细胞生长因子的促分裂作用。B)评价艾滋病毒-1病毒产品的作用 TAT和gp120对肾脏生长、bFGF合成和释放的影响。C)定义 HIV感染诱导的蛋白水解酶是否可能促进bFGF 从肾细胞和细胞外基质释放。我们预计将确定 HIV-1病毒产物对肾脏碱性成纤维细胞生长因子活性和细胞生长的影响 组织。3.确定碱性成纤维细胞生长因子及其受体在血管内皮细胞生长中的作用 HIVAN在HIV转基因小鼠中的致病机制A)定义地形 碱性成纤维细胞生长因子低亲和力结合部位和高亲和力结合部位的分布和数量 对照和转基因肾脏。B)确定新的碱性成纤维细胞生长因子结合蛋白 在转基因RTEC中。C)测定肾脏碱性成纤维细胞生长因子基因的高表达 亲和力受体(FGFR-1、FGFR-2)。D)确定碱性成纤维细胞生长因子在体内的作用 肾脏生长和HIV表达。E)评估阻断碱性成纤维细胞生长因子低水平的治疗 肾组织中亲和力受体或碱性成纤维细胞生长因子基因表达。我们预计 这些实验确定了碱性成纤维细胞生长因子之间的相互关系 肾组织蓄积和肾脏生长，并测试潜力 预防HIVAN进展的治疗方法。