PDGF-D INDUCED MODELS OF MESANGIAL GLOMERULOPATHY

描述（由申请方提供）：系膜增生性肾小球肾炎，最常见的是含有伊加和补体的免疫复合物沉积的结果（伊加肾病），是全球最常见的肾小球肾炎形式。目前缺乏一个良好的小鼠模型的病理事件发生在这种类型的损伤序列。一个小鼠模型，将概括和表现出肾小球系膜细胞增殖和肾小球系膜基质的生产和修复能力的基本特征将是特别有价值的。基于初步的数据，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的亚型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，以递送PDGF基因，其表达将导致PDGF-D的系统性过量产生，并将创建具有可调控的PDGF-D过量产生的转基因小鼠。预期两种模型均通过PDGF-D结合由小鼠和人的系膜细胞组成型表达的PDGF受体产生系膜增殖改变。我们使用形态学技术来表征这些系膜增生模型的启动和这种类型的肾小球损伤的演变，使用基因芯片微阵列分析来识别与这种损伤发生的肾小球基因表达的模式，并将使用这些模型来研究生长因子配体/受体途径的特定干预措施的影响，以修改疾病表达。

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.