Project 435913

Scleroderma or systemic sclerosis (scleroderma) is a complex rheumatoid disease that is characterized by defective immune system function, blood vessel damage and scarring (fibrosis) of the skin and internal organs. Fibrosis is a prominent feature of scleroderma and involves excessive production of extracellular matrix proteins, such as collagen and fibronectin, leading to disruption of normal tissue structure and eventually organ failure. Fibrosis has a significant impact on the quality of life of scleroderma patients and much research effort has been put towards developing therapies that can block or reverse fibrosis. Transforming growth factor-beta (TGF-beta) is a protein produced by cells of the body that is important for the development and maintenance of healthy tissues. Abnormal stimulation of TGF-beta action is thought to be involved in many fibrotic disorders including scleroderma. We have identified a protein named CD109 that binds to TGF-beta and neutralizes its biological activity in human skin cells. We have generated a shorter version of the CD109 protein (a CD109-based peptide) and found that this shorter version or peptide can reduce fibrosis in skin and lung cells. Our research goal is to characterize the above peptide molecule to determine its potential to reduce experimental fibrosis in human skin and lung tissue donated by scleroderma patients and in animal models of scleroderma, and to understand how (mechanism by which) this molecule reduces fibrosis. The proposed research will allow us to assess the potential this molecule to decrease or block fibrosis in scleroderma patients. The results from the proposed work may also have application to reduce fibrosis in other organs such as the kidney and liver.