The proteoglycan decorin is a key biological modulator of extracellular matrix assembly and cell growth in health and in important pathological conditions like fibrotic disease and cancer. We reported that human decorin, delivered by intravascular injection or by skeletal muscle- based gene transfer is therapeutic in inhibiting fibrosis in experimental glomerulonephritis. These exciting results make decorin, a natural human protein, a novel candidate to treat a number of important human fibrotic diseases including progressive kidney diseases such as diabetic nephropathy and glomerulonephritis. The goal of this application is to advance understanding of decorin biology by elucidating molecular mechanisms by which decorin regulates extracellular matrix assembly in vitro and in vivo. Major factors that have previously limited decorin research including insufficient high quality recombinant decorin and the absence of a decorin knockout mouse have been overcome by the establishment of strong collaborations that will provide these important tools. We will test the hypothesis that decorin is a multifunctional regulatory molecule that exerts its antifibrotic effects by simultaneously acting on several targets including: binding to collagen, suppressing cell proliferation and negatively regulating the fibrogenic cytokine TGF-beta and that the decorin knock out mouse will show increased susceptibility to fibrotic disease that can be reversed by decorin. Specifically we will do the following: 1) Determine if the decorin knockout mouse is more susceptible to fibrotic disease associated with anti-glomerular basement membrane glomerulonephritis and unilateral ureteral obstruction and whether the susceptibility can be reversed by administration of recombinant decorin 2) Produce recombinant decorin and biglycan as proteoglycans, core proteins and mutant forms in which various protein binding sites have been disrupted and test the functional properties of these molecules in vitro 3) Use the various mutant forms of decorin to analyze the mechanisms that underlie decorin's antifibrotic effects in vivo, including collagen binding, suppression of cell proliferation and neutralization of TGF-beta. The significance of this application is that it will apply new knowledge and technology to an area of investigation that is directly relevant to improved understanding of the pathogenesis of fibrotic diseases. Furthermore, this work will likely provide insights into decorin's antifibrotic effects that may suggest additional novel therapeutic interventions in important human fibrotic diseases as well as cancer.
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