Receptor Antagonists of Transforming Growth Factor-beta

The transforming growth factor betas (TGF-B) belong to a family of proteins that aremultifunctional in activity. They act as simulators and inhibitors of cell replication, control the synthesisand deposition of extracellular matrix, and regulate the immune system. They are actively involved inembryonic development and wound repair. Aberrant regulation of TGF-B activity results in overeexpress-ion of this potent cytokine and there are a number of fibroproliferative diseases associated-with its highlevel. The proposed research is aimed atdeveloping a therapeutic molecule that will bind TGF-B with high affinity and inactivate it from bindingto its biological receptors, in effect neutralizing the biological activity of TGF-B. Using the type II andtype III TGF-B receptors as such molecules, this study proposes to: 1) prepare soluble monomericreceptors in E. coli and mammalian expression systems; 2) prepare soluble homodimeric andheterodimeric receptor chimeric molecules (receptor/lgG fusions) in mammalian expression systems; 3)produce mutant forms of soluble receptors; and 4) compare these receptors in TGF-B binding andneutralization assays. It is believed that these experiments will yield an ideal candidate therapeutic totreat disease characterized by overexpression of TGF-B.