The nuclear receptor TR4 orchestrates cytoskeletal organization in a Gα12/ROCK-dependent manner to promote myofibroblast differentiation and tissue fibrosis in systemic sclerosis

• Applicant: Dr. Yun Zhang
• Subject Area: Rheumatology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525054759

The aim of the proposed study is to investigate the role of TR4 in the pathogenesis of fibrotic tissue remodeling with a particular focus on SSc as a prototypical systemic fibrotic disease. We evaluate the regulation of TR4 expression by TGFβ signaling, the molecular mechanisms, by which TR4 regulates TGFβ-induced fibroblast activation and the efficacy of targeted inactivation of TR4 on dermal and pulmonary fibrosis in complementary mouse models. We demonstrate in our preliminary results that TR4 is overexpressed in SSc in a TGF-dependent manner, that TR4 is implicated in fibrotic tissue remodeling as inactivation of TR4 decreases the expression of multiple, fibrosis-relevant genes, prevents myofibroblast differentiation, reduces the release of collagen and ameliorates bleomycin-induced dermal and pulmonary fibrosis as well as TBRIact-induced dermal fibrosis. To characterize the profibrotic signaling pathways regulated by TR4 in more detail and validate TR4 as a potential target for antifibrotic therapies, specifically, we plan to further characterize the role of TR4 on fibroblast-to-myofibroblast differentiation using a multi-omics approach with RNA-seq and Ribo-seq. Previous RNA-Seq results showed that identified profound changes in the mRNA levels of multiple genes and functional processes implicated in cytoskeletal organization and Rho/ROCK activity. Thus, we will investigate the effects of TR4 on G12/ROCK signaling as a molecular mechanism underlying the regulatory effects of TR4 on myofibroblast differentiation. Moreover, we will evaluate of the anti-fibrotic effects of fibroblast-specific Tr4 knockdown in a murine model of chronic graft-versus-host-disease (cGvHD). In the end, the efficacy of TR4 inactivation on fibrotic tissue remodeling in advanced human in vitro model systems will be assessed.

• DFG Programme: Research Grants