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.
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