SPECIFIC INHIBITORS OF GLOMERULONEPHRITIS

THE EXTRACELLULAR MATRIX IS A COMPLEX SUPERSTRUCTURE OF MACROMOLECULES COMPOSED OF GLYCOPROTEINS, PROTEOGLYCANS, ANDCOLLAGEN AND SURROUNDS ALMOST EVERY CELL IN THE BODY. THE INAPPROPRIATE OVEREXPRESSION OF EXTRACELLULAR MATRIX IN CERTAIN TISSUE HAS BEEN IMPLICATED IN A VARIETY OF HUMAN DISEASES, INCLUDING GLOMERULONEPHRITIS AND PULMONARY FIBROTIC DISEASE. TRANSFORMING GROWTH FACTOR (TGF)-BETA-1 HAS BEEN SHOWN TO CAUSE THE ACCUMULATION OF EXTRACELLULAR MATRIX BY INCREASINGTHE EXPRESSION OF MATRIX COMPONENTS, AS WELL AS BY DECREASING NORMAL MATRIX DEGRADATION. ANTI-TGF-BETA-1 ANTISERA AND THE PROTEOGLYCAN, DECORIN, BIND TGF-BETA-1 AND NEUTRALIZE ITS EFFECT ON MATRIX OVEREXPRESSION, THUS REVERSING THE HISTOLOGICAL MANIFESTATION OF EXPERIMENTAL GLOMERULONEPHRITIS IN RATS. IN THIS PROJECT, SYNTHETIC PEPTIDES AND RECOMBINANT PROTEIN FRAGMENTS BASED ON THE DOMAIN STRUCTURE OF HUMAN DECORIN WILL BE TESTED FOR THEIR ABILITY TO BIND THE NEUTRALIZE TGF-BETA-1 BIOLOGICAL ACTIVITY IN VITRO AND IN VIVO. THESE STUDIES WILL LEAD TO THE IDENTIFICATION OF THE MINIMAL DOMAIN OF THE DECORIN CORE PROTEIN REQUIRED FOR REVERSAL OF TGF-BETA-1 EFFECTS AND MAY PROVIDE AN EFFECTIVE, NONTOXIC THERAPY FOR CERTAIN TYPES OF GLOMERULONEPHRITIS AND OTHER MATRIX-RELATED DISEASES.