The role of alpha7 nicotinic acetylcholine receptor in fibrosis

• Applicant: Dr. Agatha Stegemann
• Subject Area: Dermatology
• Term: since 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 184054425

Systemic scleroderma is a prototypical chronic fibrotic skin disease and represents one of the biggest challenges for dermatology. A novel strategy for the therapy of this disease could be distinct neuroendocrine mediators and derivatives. During the 1st funding period we showed that tropisetron, an approved antiemetic and serotonin receptor antagonist, suppressed collagen synthesis and myofibroblast differentiation of human dermal fibroblasts (HDF) induced by the profibrotic cytokine transforming growth factor (TGF)-beta1. Interestingly, this effect is not mediated by serotonin receptors but via the alpha7 nicotinic acetylcholine receptor (alpha7nAchR). The suppressive effect of tropisetron on skin fibrosis was validated in the bleomycin mouse model of scleroderma. In the present follow-up project we will investigate 1.) by which molecular mechanism tropisetron suppresses TGF-beta1-induced collagen synthesis in HDF, focusing on the activator protein-1 signaling pathway, 2.) if tropisetron attenuates experimentally induced skin fibrosis in a non-inflammatory setting (in the tight-skin I and Ad-TBRIact mouse model), 3.) the role of the alpha7nAchR in experimentally induced fibrosis in vivo employing alpha7nAchR-deficient mice, and 4.) whether tropisetron and classical alpha7nAchR agonists can modulate extracutaneous fibrosis (lung and liver). These investigations will create the basis for a novel therapy of human fibrotic diseases with alpha7nAchR agonists.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Markus Böhm