Accumulation of extracellular matrix as scar material leading to tissue destruction is a central feature of progressive glomerulonephritis and other chronic fibrotic diseases involving the kidney, lung, liver, heart, skin, eye, bone marrow and central nervous system. Progressive fibrosis often destroys function of the organ as happens in endstage renal disease, pulmonary fibrosis and liver cirrhosis. Such chronic fibrotic diseases are major causes of human suffering and death, and add billions of dollars to the national cost of health care. The molecular events underlying the pathogenesis of fibrosis are not understood and, consequently there are few or no effective therapies for these disorders. Research, as proposed in this application, to elucidate the molecular basis of fibrosis is critically needed. A growing body of evidence suggests that overproduction of transforming growth factor-beta (TGF-beta), a cytokine vital to tissue repair, may be responsible for the scarring in chronic kidney diseases. Our laboratory has developed a model of progressive glomerulonephritis that closely resembles human disease. We also have developed a potential antifibrotic agent, the human proteoglycan decorin, that blocks the action of TGF-beta. In this research application we propose 1) to understand the molecular basis of TGF-beta overproduction in the disease and 2) to elucidate the mechanism of decorin's antifibrotic actions. We propose to provide this new information by accomplishing the following Specific Aims: 1) To further investigate and characterize our progressive model of glomerulonephritis, 2) To determine whether decorin's antifibrotic effect is due solely to TGF-beta binding or whether simultaneous attachment to matrix via collagen fibrils is also a requirement, 3) To determine if if decorin administration can prevent, limit or reverse sustained TGF-beta expression and progressive fibrosis in the animal model of chronic glomerulonephritis. The therapeutic efficacy of decorin will be tested at different stages in the experimental model. The results of these experiments will be invaluable in predicting the future of decorin as an antifibrotic agent. This research proposal is aimed at elucidating the pathogenesis of fibrosis and testing an experimental treatment. Our findings may offer considerable hope to those who suffer from progressive glomerulonephritis and other fibrotic diseases.
Showing the most recent 10 out of 25 publications
