In the United States 45,000 people develop kidney failure each year at an average cost of treatment of $35,000 per patient. Currently there are 195,000 patients suffering from kidney failure and, by the year 2000, there will be over 300,000 kidney-failure patients whose treatment will cost the Federal Government more than 10 billion dollars. Thus diseases that cause kidney failure are major sources of human suffering and death and add billions of dollars to the cost of health care. One reason why so many patients develop kidney failure is the lack of an effective agent to block the fibrosis that destroys kidney function. Research, as proposed in this application, to determine the causes of fibrosis and develop an antifibrotic therapy, is critically needed. Accumulation of extracellular matrix in the form of scar material underlies the development of fibrosis in progressive kidney diseases that lead to kidney failure and the need for dialysis or transplantation. Extracellular matrix is produced by cells and is a glue-like materia, composed of a variety of proteins. This """"""""glue"""""""" surrounds all cells in the body, allowing them to """"""""stick"""""""" to each other to form tissues, and it is produced at the site of tissue injury to enhance healing. A body of evidence suggests that the production of extracellular matrix in health and disease is regulated by a molecular, transforming growth factor-beta (TGF-beta). As summarized in the Progress Report, our laboratory has shown the involvement of TGF- beta in the pathogenesis of human and experimental kidney fibrosis. We wish to better understand the molecular basis of TGF-beta's fibrogenic actions and to test the therapeutic potential of a protein, decorin, as a TGF-beta antagonist and anti-fibrotic agent. In this application we propose to provide this new information by accomplishing the following specific aims: 1) To continue investigation of decorin as an antifibrotic agent to treat kidney fibrosis. 2) To continue investigation of the plasmin protease system and integrin matrix receptors in kidney fibrosis. 3) To investigate the role of TGF-beta receptors and TGF-beta latency- associated proteins in kidney fibrosis. 4) To investigate the measurement of TGF-beta concentrations as a prognostic marker of kidney fibrosis. Methods involve the use of experimental models of acute and chronic glomerulonephritis and diabetic nephropathy that exist in our laboratory.
Each specific aim will be investigated by modern cell and molecular biological techniques including tissue culture, biosynthetic labeling, immunostaining and histochemistry, northern analysis and polymerase chain reaction. Decorin will be produced by recombinant DNA technology. This research is aimed at understanding the molecular pathogenesis of fibrosis and testing a potential anti-fibrotic agent. our findings may offer hope for those who suffer from diseases that lead to kidney failure.
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