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

核受体 TR4 以 Gα12/ROCK 依赖性方式协调细胞骨架组织，以促进系统性硬化症中的肌成纤维细胞分化和组织纤维化

• 批准号: 525054759
• 负责人: Dr. Yun Zhang
• 金额: --
• 依托单位: Klinik für Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/525054759?language=en
• 关键词: nuclear; receptor; TR4; orchestrates; cytoskeletal

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.

本研究的目的是研究TR 4在纤维化组织重塑发病机制中的作用，特别关注SSc作为一种典型的系统性纤维化疾病。我们评估了TGFβ信号对TR 4表达的调节，TR 4调节TGFβ诱导的成纤维细胞活化的分子机制，以及在互补小鼠模型中靶向灭活TR 4对皮肤和肺纤维化的功效。我们在我们的初步结果中证明，TR 4在SSc中以TGF β依赖性方式过表达，TR 4参与纤维化组织重塑，因为TR 4的失活降低了多种纤维化相关基因的表达，阻止了肌成纤维细胞分化，减少了胶原蛋白的释放，并改善了博来霉素诱导的皮肤和肺纤维化以及TBRIact诱导的皮肤纤维化。为了更详细地表征由TR 4调节的促纤维化信号传导途径并验证TR 4作为抗纤维化治疗的潜在靶点，我们计划使用RNA-seq和Ribo-seq的多组学方法进一步表征TR 4对成纤维细胞向成肌纤维细胞分化的作用。先前的RNA-Seq结果表明，确定了涉及细胞骨架组织和Rho/ROCK活性的多个基因和功能过程的mRNA水平的深刻变化。因此，我们将研究TR 4对G β 12/ROCK信号传导的影响，作为TR 4对肌成纤维细胞分化的调节作用的分子机制。此外，我们将评估成纤维细胞特异性Tr 4敲低在慢性移植物抗宿主病（cGvHD）小鼠模型中的抗纤维化作用。最后，将评估TR 4失活对晚期人体外模型系统中纤维化组织重塑的功效。