Systemic sclerosis is an autoimmune disease, characterized by progressive fibrosis of the skin and internal organs. There is currently no FDA-approved agent to prevent the progression of fibrosis in systemic sclerosis. The pathogenesis of systemic sclerosis involves a complex interplay of abnormalities of the immune system, blood vessels and fibroblasts. One well-studied mechanism of fibrosis in systemic sclerosis consists in the excessive activation of the transforming growth factor beta (TGFbeta) signaling pathway in fibroblasts, which leads to excessive collagen deposition and transformation of fibroblasts in alpha-smooth muscle actin expressing myofibroblasts. Our laboratory focuses on protein tyrosine phosphatases, enzymes that control signal transduction by removing phosphate from phosphorylated tyrosines thus balancing the action of protein tyrosine kinases. The role of tyrosine phosphatases in systemic sclerosis has remained mostly unaddressed. This project stems from the observation that a tyrosine phosphatase called PTP4A1 is overexpressed in dermal fibroblast from systemic sclerosis patients compared to normal fibroblasts. Our preliminary data suggest that PTP4A1 plays a pro-fibrotic function in dermal fibroblasts ex vivo and in vivo by promoting TGFbeta signaling. This grant proposal is designed to collect pilot critical information about the molecular mechanism of action of PTP4A1 in TFGbeta signaling (Aim 1) and the ability of PTP4A1 to promote experimental fibrosis in vivo (Aim 2). The long- term goal is to validate PTP4A1 and/or its downstream pathway as possible targets to prevent fibrosis in systemic sclerosis.
We found that a protein called PTP4A1 is present at higher levels in skin cells from patients with systemic sclerosis, an autoimmune disease characterized by progressive scarring of the skin and internal organs. The objective of this project is to gather pilot evidence that PTP4A1 promotes the scarring process in systemic sclerosis. The long-term goal is to design novel therapeutics against this protein or other related players to help control scarring in systemic sclerosis.
| Sacchetti, Cristiano; Bai, Yunpeng; Stanford, Stephanie M et al. (2017) PTP4A1 promotes TGF? signaling and fibrosis in systemic sclerosis. Nat Commun 8:1060 |
