SPECIFIC INHIBITORS OF GLOMERULONEPHRITIS

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Transforming growth factor-beta plays a central role in the pathogenesis of a variety of fibrotic diseases including glomerulonephritis, diabetic nephritis, liver cirrhosis, and pulmonary fibrosis. Human decorin is a proteoglycan that binds and neutralizes the action of TGF-beta and prevents fibrosis in experimental animals. In addition to TGF-beta binding, decorin exhibits collagen binding and receptor-mediated internalization by cultured cells, leading to its metabolism. The mechanism of decorin action appears to involve more than TGF-beta binding because decor in peptides and fragments that bind TGF-beta do not appear to have a neutralizing effect. This proposal will use peptides and recombinant fragments of decorin to explore the role of collagen binding and receptor-mediated internalization in the mechanism of TGF-beta neutralization. Pre-clinical development of decorin as a treatment for glomerulonephritis will be initiated, including assay development and validation to support stability studies, followed by toxicology studies of decorin administered by continuous infusion into rats and primates. These studies will allow us to understand the mechanism of decorin action and provide the necessary data for filing an Investigational New Drug application to initiate clinical testing of decorin in human disease.