Glomerular Capillary Wall: Development and Disease

肾小球毛细血管壁：发育和疾病

• 批准号: 7273725
• 负责人: DALE R ABRAHAMSON
• 金额: $ 140.87万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273725
• 关键词: Alloantigen; Animal Model; Anti-Glomerular Basement Membrane Disease; Cells; Collagen; Collagen Type IV; Communication; Crystallography; Development; Disease; Elements; Embryo; Endothelial Cells; Epithelial Cells; Extracellular Matrix; Glomerular Capillary; Health; Hydra Polyps; Imaging Techniques; Integrins; Kidney; Laminin; Location; Maps; Mass Spectrum Analysis; Methodology; Molecular; Mus; Mutant Strains Mice; Organogenesis; Pathogenesis; Personal Satisfaction; Phenotype; Purpose; Regulation; Renal glomerular disease; Research Design; Research Project Grants; Resource Sharing; Structure; Surface Plasmon Resonance; Time; Zebrafish; cell assembly; design; glomerular basement membrane; glomerular filtration; in vivo; knock-down; molecular recognition; mouse model; podocyte; programs; transgene expression

Description: The kidney glomerular capillary wall is comprised of three elements: (1) an inner endothelial cell layer; (2) the glomerular basement membrane (GBM); and (3) an outer epithelial cell layer (podocytes). That this unique structure constitutes the glomerular filtration barrier has been well established, but how this structure develops during kidney organogenesis, is maintained in maturation normally, and becomes damaged in disease, is not fully understood. The purpose of our application is to establish a focused and complementary group of research projects that will define the development and assembly of the GBM and the molecular pathogenesis underlying selected glomerular diseases. Specifically, Project 1 will examine abnormal glomerular phenotypes in certain laminin and collagen IV mutant mice and rescue these phenotypes through metanephric grafting and inducible, cell-selective transgene expression strategies. Project 2 will study type IV collagen network formation and interaction with glomerular cell integrins using mass spectrometry, x-ray crystallography, and surface plasmon resonance, in combination with classic molecular and cellular methodologies. Project 3 will map the molecular location of pathogenic Goodpasture and Alport alloantigens on type IV collagen, examine the development of anti-GBM disease in a mouse expressing humanized type IV collagen, and in an Alport mouse model. Project 4 will examine the molecular regulation of extracellular matrix assembly and cell-matrix interactions in vivo in hydra and Zebrafish embryos as simplified model organisms, using antisense knock down and real-time imaging techniques, among other approaches. The Program is designed to promote extensive communication and sharing of resources among the Projects, which are also supported by an Administrative Core (A) and a Molecular Recognition Core (B). We anticipate that this Program will reveal fundamentally new information regarding glomerular structure in health and disease.

描述：肾小球毛细血管壁由三个部分组成：（1）内皮细胞层； (2)肾小球基底膜(GBM)； (3) 外上皮细胞层（足细胞）。这种独特的结构构成了肾小球滤过屏障，这一点已经得到充分证实，但这种结构如何在肾脏器官发生过程中发育、正常维持成熟以及在疾病中受损的情况尚不完全清楚。我们申请的目的是建立一个有针对性和互补性的研究项目组，这些项目将定义 GBM 的发育和组装以及选定肾小球疾病的分子发病机制。具体来说，项目 1 将检查某些层粘连蛋白和 IV 型胶原突变小鼠的异常肾小球表型，并通过后肾移植和可诱导的细胞选择性转基因表达策略来挽救这些表型。项目 2 将利用质谱、X 射线晶体学和表面等离振子共振，结合经典的分子和细胞方法，研究 IV 型胶原网络的形成以及与肾小球细胞整合素的相互作用。项目 3 将绘制 IV 型胶原蛋白上致病性 Goodpasture 和 Alport 同种抗原的分子位置，检查表达人源化 IV 型胶原蛋白的小鼠和 Alport 小鼠模型中抗 GBM 疾病的发展。项目 4 将使用反义敲除和实时成像技术等方法，研究水螅和斑马鱼胚胎作为简化模型生物体内细胞外基质组装和细胞基质相互作用的分子调节。该计划旨在促进项目之间的广泛沟通和资源共享，并得到行政核心 (A) 和分子识别核心 (B) 的支持。我们预计该计划将揭示有关健康和疾病中肾小球结构的全新信息。