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.
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