PDGF-D INDUCED MODELS OF MESANGIAL GLOMERULOPATHY

PDGF-D 诱导的系膜肾小球病模型

• 批准号: 6951083
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951083
• 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（由申请人提供）：系血管增殖性肾小球肾炎，通常是含有IgA和补体的免疫复合物沉积的结果（IgA肾病），是世界范围内最常见的肾小球肾炎形式。目前还缺乏一个良好的小鼠模型来描述这种类型损伤中发生的事件的病理顺序。一个能够概括和展示系膜细胞增殖、系膜基质产生和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产生最近发现的血小板衍生生长因子（PDGF）， PDGF- d的系统性和局部过表达来创建这样一个模型。我们将利用已建立的方法来创建病毒载体来传递PDGF基因，其表达将导致PDGF- d的系统性过量生产，并将创建具有可调节的PDGF- d过量生产的转基因小鼠。这两种模型都有望通过PDGF- d结合PDGF受体-产生系膜增殖改变，PDGF受体-由小鼠和人类系膜细胞组成表达。我们使用形态学技术来表征这些系膜增殖模型，以研究这种类型肾小球损伤的发生和进化，使用基因芯片微阵列分析来确定这种损伤发生的肾小球基因表达模式，并将使用这些模型来研究特定干预对生长因子配体/受体途径的影响，以改变疾病表达。

项目成果

Induction of progressive glomerulonephritis by podocyte-specific overexpression of platelet-derived growth factor-D.

• DOI: 10.1038/ki.2011.278
• 发表时间: 2011-12
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Claudia R C van Roeyen;F. Eitner;P. Boor;M. Moeller;U. Raffetseder;Lydia Hanssen;Eva Bücher;L. Villa;M. Banas;K. Hudkins;C. Alpers;T. Ostendorf;J. Floege