PDGF-D INDUCED MODELS OF MESANGIAL GLOMERULOPATHY

PDGF-D 诱导的系膜肾小球病模型

• 批准号: 6863291
• 负责人: CHARLES E ALPERS
• 金额: $ 15.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863291
• 关键词: IgA nephropathy; biological signal transduction; biotechnology; disease /disorder model; gene expression; genetically modified animals; glomerulonephritis; growth factor receptors; immune complex; immunocytochemistry; in situ hybridization; kidney cell; laboratory mouse; ligands; microarray technology; northern blottings; platelet derived growth factor; protein isoforms; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): Mesangioproliferative glomerulonephritis, most often the result of deposition of immune complexes containing IgA and complement (IgA nephropathy), is the most common form of glomerulonephritis encountered worldwide. A good murine model of the pathologic sequence of events that occurs in this type of injury is currently lacking. A mouse model that would recapitulate and demonstrate essential features of mesangial cell proliferation and production of mesangial matrix and the capacity for repair would be particularly valuable. Based on preliminary data, we plan to create such a model by utilizing two complementary approaches to produce systemic and localized overexpression of a recently discovered isoform of platelet derived growth factor (PDGF), PDGF-D. We will utilize established methods to create viral vectors to deliver PDGF genes whose expression will result in systemic overproduction of PDGF-D, and will create a transgenic mouse with regulatable overproduction of PDGF-D. Both models are expected to produce mesangial proliferative alterations through PDGF-D binding of the PDGF Receptor- , constitutively expressed by mesangial cells in mice and humans. We use morphologic techniques of characterize these mesangia proliferative models for the initiation and evolution of this type of glomerular injury, use gene chip microarray analysis to identify patterns of glomerular gene expression that occur with this injury, and will use these models to study the effects of specific interventions in growth factor ligand/receptor pathways to modify disease expression.

描述(申请人提供)：系膜增生性肾小球肾炎，最常见的结果是含有IgA和补体的免疫复合物的沉积(IgA肾病)，是全球最常见的肾小球肾炎形式。目前尚缺乏一种良好的小鼠模型来研究在这种类型的损伤中发生的一系列事件。一个概括和展示系膜细胞增殖和系膜基质产生的基本特征以及修复能力的小鼠模型将特别有价值。基于初步数据，我们计划通过利用两种互补的方法来创建这样的模型，以产生最近发现的血小板衍生生长因子(PDGF)的异构体PDGF-D的系统性和局部性过度表达。我们将利用已建立的方法创建病毒载体来传递PDGF基因，这些基因的表达将导致全身PDGF-D的过度生产，并将创造出一种可调节的PDGF-D过度生产的转基因小鼠。这两种模型都有望通过PDGF-D与PDGF受体的结合而产生系膜增生性改变，该受体由小鼠和人类的系膜细胞组成地表达。我们使用形态学技术来描述这种类型的肾小球损伤的起始和演变的系膜增殖模型，使用基因芯片微阵列分析来确定与这种损伤相关的肾小球基因表达模式，并将使用这些模型来研究在生长因子配体/受体通路中的特定干预对改变疾病表达的影响。