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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG4-GMA-1 (01))
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Ketchum, Christian J
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Huang, Yufeng; Border, Wayne A; Lawrence, Daniel A et al. (2009) Mechanisms underlying the antifibrotic properties of noninhibitory PAI-1 (PAI-1R) in experimental nephritis. Am J Physiol Renal Physiol 297:F1045-54
Huang, Y; Border, W A; Lawrence, D A et al. (2006) Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis. Kidney Int 70:515-22
Huang, Y; Wongamorntham, S; Kasting, J et al. (2006) Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 69:105-13
Gaedeke, Jens; Noble, Nancy A; Border, Wayne A (2005) Curcumin blocks fibrosis in anti-Thy 1 glomerulonephritis through up-regulation of heme oxygenase 1. Kidney Int 68:2042-9
Yu, Ling; Border, Wayne A; Anderson, Ian et al. (2004) Combining TGF-beta inhibition and angiotensin II blockade results in enhanced antifibrotic effect. Kidney Int 66:1774-84
Peters, Harm; Border, Wayne A; Ruckert, Matthias et al. (2003) L-arginine supplementation accelerates renal fibrosis and shortens life span in experimental lupus nephritis. Kidney Int 63:1382-92
Huang, Yufeng; Haraguchi, Masashi; Lawrence, Daniel A et al. (2003) A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis. J Clin Invest 112:379-88
Yu, Ling; Border, Wayne A; Huang, Yufeng et al. (2003) TGF-beta isoforms in renal fibrogenesis. Kidney Int 64:844-56
Haraguchi, M; Border, W A; Huang, Y et al. (2001) t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis. Kidney Int 59:2146-55
Border, W A; Noble, N (2001) Maximizing hemodynamic-independent effects of angiotensin II antagonists in fibrotic diseases. Semin Nephrol 21:563-72

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