The overall goal of this project is the preclinical development of a novel Rho kinase inhibitor (TRX-101) as a new therapy for scleroderma/systemic sclerosis (SSc). SSc is a chronic disease of unknown etiology characterized by severe and often progressive fibrosis affecting the skin and in some cases internal organs. Since there is no approved anti-fibrotic drug for SSc, the current mainstay of treatment has been non-selective immunosuppression. Cyclophosphamide is the main treatment for progressing skin involvement and is effective in early stages of the disease but does not appear to provide benefits at later stages. Furthermore, nonspecific immunosuppressive drugs are associated with significant morbidity and mortality. Hence, new approaches that may provide both anti-inflammatory and anti-fibrotic effects are urgently needed. Rho kinase inhibitors such as fasudil (approved in Japan for cerebral vasospasm) have proven effective in various preclinical models of fibrosis and inflammation;however Rho kinase inhibitors have not yet been tested in SSc. Because TRX-101 is much more potent and specific for Rho kinase as compared to fasudil, it has the potential to become a much more effective therapeutic capable of suppressing both fibrotic and inflammatory processes in SSc. There are three aims in this proposal: 1) Evaluate bioavailability, pharmacokinetics and potential toxicity o orally administered TRX-101 in mice. 2) Test the anti-fibrotic effects of TRX-101 on cultured skin fibroblasts derived from SSc patients. 3) Evaluate the therapeutic efficacy of TRX-101 in a mouse model of SSc. The results of these studies will provide the basis for future clinical development of TRX-101 as a novel therapy for SSc. Because of its unique mechanism of action and potent anti-fibrotic and anti-inflammatory properties, this drug candidate could provide SSc patients with a new therapeutic option of special benefit for patients that have failed the usual suboptimal immunosuppressive treatments.