POS0148 STIFFNESS INDUCED PROGRESSION OF FIBROSIS BY SORBIN AND SH3 DOMAIN-CONTAINING PROTEIN2 IN SYSTEMIC SCLEROSIS

Background Persistently activated fibroblasts status leads to progressive extracellular matrix (ECM) deposition and tissue remodeling. The hallmark of systemic sclerosis (SSc) is collagen accumulation in organs, mainly skin lung. Despite intensive progress understanding disease occurence, SSc remains an intriguing with unknown pathology high mortality. Sorbin SH3 domain-containing protein2, encoded by SORBS2 a key member the sorbin homology family adapter scaffold proteins. Recent studies suggest that plays role cardiac disease, however there no available data about its fibrotic conditions. Objectives We aimed investigate pathogenesis SSc. Methods To identify molecules specifically upregulated persistently fibroblasts, human were chronically stimulated TGF-β analyzed RNA-sequencing. evaluate functional implication elasticity on transcriptome multiwell stiffness assays performed. expression was further samples patients murine models fibrosis. Fibroblast specific knockout mice challenged bleomycin induce lung Further readouts like content, thickness, myofibroblast count, CT scans Results Upon chronic stimulation normal we identified SORBS2, as significantly molecule. implicated cytoskeletal organization, cell adhesion different signaling pathways. Moreover, induced upregulation mRNA level fibroblasts. Deletion led change diameter fibers modified elastic index tissue. not only elevated animal fibrosis, but also patients. (KO) developed less fibrosis upon challenge comparison wild type (WT), assessed measurement dermal counts hydroxyproline content. Col1a1 , Col1a2 αSMA lower KO WT mice. Similarly, fibroblast showed protective effects lungs statistically significant changes Conclusion engaged vicious circle Triggered stimulation, increasing matrix. This levels resulting into production ECM products. Deleting has potent antifibrotic As most currently used therapeutic approaches are focussed early stages might be interesting new target established REFERENCES: NIL. Acknowledgements: Disclosure Interests None Declared.