Targeted inhibition of tyrosine-protein phosphatase SHP2 as a potential approach for the treatment of fibrosis

• Applicant: Professor Dr. Jörg Hans Wilhelm Distler
• Subject Area: Rheumatology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 392500703

Fibrotic diseases contribute to up to 45% of deaths in the developed world and impose a major socioeconomic burden on modern societies. Systemic sclerosis (SSc) is a prototypical idiopathic systemic fibrosing disease with a high morbidity and mortality rate. As for other fibrotic diseases, SSc is characterized by an accumulation of myofibroblasts, which release excessive amounts of extracellular matrix. Although key factors of fibroblast activation such as transforming growth factor-beta (TGFbeta) have been identified, the molecular mechanisms underlying the persistent activation of myofibroblasts in fibrotic disease are incompletely understood and effective targeted therapies are not available for most fibrotic diseases. We provide first evidence that the tyrosine phosphatase SHP2 might play a central role in the pathogenesis of fibrotic diseases such as SSc. Inactivation of SHP2 signaling prevents the TGF-bata mediated activation of JAK2 / STAT3 signaling to prevent myofibroblast differentiation and collagen release. Inactivation of SHP2 by genetic or pharmacologic approaches inhibits TGF-beta-dependent fibroblast activation and ameliorates experimental fibrosis. We aim to further characterize the molecular mechanisms of SHP2 signaling in fibrotic diseases and to validate the SHP2 as a therapeutic target in fibrotic diseases. We plan to further analyze the anti-fibrotic effects of fibroblast-specific knockdown of SHP2 in complementary mouse models of fibrosis, to identify the molecular mechanisms underlying the differential expression of SHP2 in SSc, to characterize the regulation of JAK2 / STAT3 signaling by SHP2 and to evaluate the anti-fibrotic effects of pharmacologic inhibition of SHP2. Our findings may have translational implications as small molecule inhibitors of SHP2 are currently evaluated for clinical use in cancer.

• DFG Programme: Research Grants