BFGF Low Affinity Receptors and HIVAN

BFGF 低亲和力受体和 HIVAN

基本信息

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
项目类别：
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

项目摘要

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.

在赠款的最后一个时期，我们发现肝素结合生长因子（HBGF）积累与HIV相关的HIV感染儿童和HIV-TG大鼠/小鼠的循环和肾脏组织中肾病（Hivan）。基于这些数据，我们假设硫酸乙酰肝素蛋白聚糖（HSGP）位于肾上皮细胞表面上，维持HIV-1在肾脏中的感染性，并增加招募HIV-TAT和HBGF，诱导肾上皮细胞的增殖和进展肾脏疾病。该假设的第二个推论是防止循环病毒蛋白的结合 HBGF到肾脏HSPG将改善Hivan的临床结果。将研究三个目标：目标1）定义HIV-TAT和GP120调节原发性肾小球和 HIV-TG大鼠儿童hivan模型中的管状上皮细胞，并定义了HBGF的作用过程。为了探索GP120的作用，我们将生成表达信封突变HIV-1的HIV-TG大鼠转基因。从野生型（WT）和HIV-TG收获大鼠将被腺病毒-TAT（RAD-TAT）或对照载体感染。这些细胞/MK将在体外遵循或在成年WT或HIV-TG大鼠的肾囊下移植，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结合，调节培养的主要的生长速率和分化从和没有Hivan的儿童收获的足细胞和肾小管上皮细胞。我们已经发展了培养培养的新方法与Hivan儿童分化的足细胞，并评估其增长率在存在或不存在HBGF或GP120的情况下，用RAD-TAT或NEF载体感染后。我们也会定义原代人肾上皮细胞是否表达HIV-1病毒产物，并验证目标1。目标3）确定五峰二硫酸盐（PPS）是单独的还是与蛋白酶结合的抑制剂（PI）将通过阻止Tat/HBGF在体内和/或通过的活性来改善Hivan的结果防止HIV-1的附着，进入和/或融合到从中收获的培养的肾上皮细胞 Hivan的孩子。这些研究将表明，生长因子释放到HIV的循环中受感染的儿童可以加速Hivan的进展，并测试针对该疾病的新疗法。