BFGF Low Affinity Receptors and HIVAN

BFGF 低亲和力受体和 HIVAN

• 批准号: 7539422
• 负责人: PATRICIO E RAY
• 金额: $ 14.47万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539422
• 关键词: AIDS-Associated Nephropathy; Adult; Affinity; Binding; Binding Proteins; Biological; Blood Circulation; Cells; Child; Childhood; Childhood Injury; Clinical; Data; Differentiation and Growth; Disease; Epithelial Cells; Extracellular Space; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibrous capsule of kidney; Gene Transfer Techniques; Genes; Goals; Grant; Growth; Growth Factor; HIV; HIV Envelope Protein gp120; HIV Receptors; HIV-1; Harvest; Heparan Sulfate Proteoglycan; Heparin Binding Growth Factor; Human; In Vitro; Infection; Injury; Kidney; Kidney Diseases; Kidney Glomerulus; Knowledge; Laboratories; Methods; Modeling; Mus; Mutate; Numbers; Outcome; Pathogenesis; Pentosan Polysulfate; Pentosan Sulfuric Polyester; Principal Investigator; Process; Protease Inhibitor; Proteins; Proteomics; Rate; Rattus; Relative (related person); Renal Tissue; Research; Role; Surface; Techniques; Testing; Transcriptional Activation; Transgenes; Transgenic Mice; Transplantation; Tubular formation; Up-Regulation; Urine; Viral; Viral Proteins; Work; base; chemokine; clinically relevant; gp-120 Antigen; improved; in vivo; injured; podocyte; prevent; programs; research study; vector; vector control

During the last period of the grant we have found an accumulation of heparin binding growth factors (HBGF) in the circulation and renal tissues of HIV-infected children and HIV-Tg rats/mice with HIV-associated nephropathy (HIVAN). Based on these data, we hypothesize that heparan sulfate proteoglycans (HSGP) located on the surface of renal epithelial cells sustain the infectivity of HIV-1 in the kidney, and increase the recruitment of HIV-Tat and HBGF inducing the proliferation of renal epithelial cells and progression of the renal disease. A second corollary of this hypothesis is that preventing the binding of circulating viral proteins and HBGF to renal HSPG will improve the clinical outcome of HIVAN. Three aims will be studied: AIM 1) To define the basic mechanisms by which HIV-Tat and gp120 modulate the growth of primary glomerular and tubular epithelial cells in an HIV-Tg rat model of childhood HIVAN, and define the role of HBGF in this process. To explore the role of gp120, we will generate HIV-Tg rats expressing an envelope mutated HIV-1 transgene. Primary podocytes and metanephric kidneys (MK) harvested from wild type (WT) and HIV-Tg rats, will be infected with adenoviral-Tat (rAd-Tat) or control vectors. These cells/MK will be followed in vitro, or transplanted under the renal capsule of adult WT or HIV-Tg rats, to determine their growth rate, and to define the role of circulating viral proteins/HBGF in this process. AIM 2) To determine how HIV-Tat, Nef, and gp120, alone or in combination with HBGF, modulate the growth rate and differentiation of cultured primary podocytes and tubular epithelial cells harvested from children with and without HIVAN. We have developed new methods to culture differentiated podocytes from children with HIVAN, and to evaluate their growth rates after infection with rAd-Tat or Nef vectors, in the presence or absence of HBGF or gp120. We will also define whether primary human renal epithelial cells express HIV-1 viral products, and validate the results of AIM 1. AIM 3) To determine whether pentosan polysulfate (PPS), alone or in combination with protease inhibitors (Pis), will improve the outcome of HIVAN by blocking the activity of Tat/HBGF in vivo, and/or by preventing the attachment, entry, and/or fusion of HIV-1 to cultured renal epithelial cells harvested from children with HIVAN. These studies will demonstrate that growth factors release into the circulation of HIV- infected children can accelerate the progression of HIVAN, and test new therapies against this disease.

在资助的最后一个时期，我们发现肝素结合生长因子（HBGF）的积累 在 HIV 感染儿童和 HIV 相关 HIV-Tg 大鼠/小鼠的循环和肾组织中 肾病（HIVAN）。根据这些数据，我们假设硫酸乙酰肝素蛋白聚糖 (HSGP) 位于肾上皮细胞表面的HIV-1维持肾脏内的感染性，并增加 HIV-Tat 和 HBGF 的募集诱导肾上皮细胞增殖和肾病进展 肾脏疾病。该假设的第二个推论是防止循环病毒蛋白的结合 HBGF 与肾 HSPG 的结合将改善 HIVAN 的临床结果。将研究三个目标： AIM 1) 定义 HIV-Tat 和 gp120 调节初级肾小球和肾小球生长的基本机制 儿童 HIVAN 的 HIV-Tg 大鼠模型中的肾小管上皮细胞，并定义了 HBGF 在此过程中的作用 过程。为了探索 gp120 的作用，我们将生成表达包膜突变的 HIV-1 的 HIV-Tg 大鼠 转基因。从野生型 (WT) 和 HIV-Tg 中收获的原代足细胞和后肾 (MK) 大鼠将被腺病毒-Tat (rAd-Tat) 或对照载体感染。这些细胞/MK将在体外进行跟踪， 或移植到成年WT或HIV-Tg大鼠的肾被膜下，以确定其生长速度，并 定义循环病毒蛋白/HBGF 在此过程中的作用。目标 2) 确定 HIV-Tat、Nef 和 gp120，单独或与 HBGF 组合，调节培养原代细胞的生长速率和分化 从患有和不患有 HIVAN 的儿童中采集的足细胞和肾小管上皮细胞。我们开发了 培养 HIVAN 儿童分化足细胞并评估其生长速度的新方法 在存在或不存在 HBGF 或 gp120 的情况下，用 rAd-Tat 或 Nef 载体感染后。我们也会 确定原代人肾上皮细胞是否表达 HIV-1 病毒产物，并验证结果 目的 1. 目的 3) 确定戊聚糖多硫酸盐 (PPS) 是否单独使用或与蛋白酶组合使用 抑制剂（Pis），将通过阻断体内 Tat/HBGF 的活性和/或通过 防止 HIV-1 附着、进入和/或融合到培养的肾上皮细胞中 患有 HIVAN 的儿童。这些研究将证明生长因子释放到艾滋病毒循环中 受感染的儿童可以加速 HIVAN 的进展，并测试针对这种疾病的新疗法。