Mutual amplification of Hedgehog and Activator Protein 1 (AP1)-signaling in Systemic Sclerosis - potential therapeutic and prognostic implications

• Applicant: Dr. Christina Bergmann
• Subject Area: Rheumatology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535409690

Fibrosing disorders such as Systemic Sclerosis (SSc) are characterized by a high morbidity and mortality and contribute to up to 45% of deaths in Western civilizations. The management of patients with fibrosing disorders is limited by the paucity of effective treatment options. Moreover, the individual disease course and risk of disease progression is hard to predict although risk factors for disease progression have been characterized on the population level. Activated fibroblasts, so-called myofibroblasts, are key effector cells in fibrotic diseases. Although profibrotic signaling pathways such AP/1 signaling and Hedgehog signaling have been identified to play a key role in fibrosing disorders such as SSc, the profound inhibition of their central mediators limited by concerns about side effects due to their broad cellular functions in particular in the setting of longterm-inhibition in a chronic disorder such as SSc. Combinations of synergistic therapies could offer a way to reduce the doses of individual drugs, resulting in reduced toxicity, but comparable or even improved efficacy. Our preliminary results for this study provide first evidence for the virtual amplification of AP1- and Hedgehog signaling in fibrotic diseases that might play a central role for aberrant fibroblast activation and progressive fibrotic tissue remodeling. We show that cJUN and GLI2 are simultaneously overexpressed in SSc fibroblasts compared to healthy fibroblasts and positively regulate each other. Inhibition of cJUN reduces Hedgehog-induced fibroblast activation and tissue fibrosis and the combined inhibition of cJUN/AP1 signaling and GLI2/hedgehog signaling shows additive anti-fibrotic effects in vivo. With the current application, we aim to further characterize the combined inhibition of cJUN/AP1-signaling and GLI2/Hedgehog signaling as potential therapeutic strategy in fibrosing disorders: We will analyze the central downstream mechanisms that mediate the additive anti-fibrotic effects of the combined inhibition of cJUN/AP1- and GLI2/Hedgehog signaling. We aim to investigate the effects of the combined inhibition of both pathways in an in vitro clinical trial using precision cut tissue slices and in a humanized three dimensional-skin model We plan to further evaluate the effects of the combined inhibition of cJUN/AP1 signaling and GLI2/Hedgehog signaling in a preclinical mouse model, that reflects further fibrotic organ manifestations and pathophysiological aspects of SSc: the model of Topoisomerase I induced skin and lung fibrosis. We aim to analyze whether the upregulation of cJUN and GLI2 in SSc skin has prognostic implications for the disease course in individual patients.

• DFG Programme: Research Grants