EGR1调控TWIST1-Sox9负反馈回路促进VICs向CBs转分化致瓣膜粘液变性的研究

主动脉瓣钙化(AVC)和二尖瓣粘液样变性(MMV)是退行性心脏瓣膜病的主要临床类型。与AVC方面所取得的巨大进展相比,MMV相关研究较少。虽已明确瓣膜间质细胞(VICs)向软骨母细胞(CBs)转分化是导致MMV的主要原因,但机制不清。新近,我们在研究VICs向骨母细胞转化致瓣膜钙化时发现,早期生长反应1(EGR1)基因通过抑制TWIST1能促进CBs核心转录因子Sox9的表达,而Sox9与TWIST1又相互抑制。据此,我们提出” EGR1调控TWIST1-Sox9负反馈回路促VICs向CBs转分化”的假说。为验证该假说,我们先后检测EGR1在CBs转分化中的作用,借助ChIP等功能实验逐级分析EGR1对TWIST1的调控、TWIST1、Sox9之间的调控，并在临床组织标本和动物模型中明确该通路在瓣膜粘液变性中的作用。通过此研究，力图阐明VICs向CBs转分化的机制，为MMV的防治提供靶点。

Aortic valve calcification (AVC) and myxomatous mitral valve (MVC) are the main clinical types of degenerative heart valve disease. Compared with the huge progress made in AVC, there are few studies on MMV. Although it has been clarified that the transdifferentiation of valve interstitial cells (VICs) into chondrocytes (CBs) is the main cause of MMV, the mechanism is unclear. Recently, during exploring the mechanism of transdiffereation from VICs into osteoblasts, we found that EGR1 gene could promote the expression of Sox9, a core transcription factor of CBs, by inhibiting TWIST1. Furthermore, Sox9 and TWIST1 mutually inhibited each other. Accordingly, we propose the hypothesis that "EGR1 regulates TWIST1-Sox9 negative feedback loop to promote VICs transdifferentiated into CBs." To test this hypothesis, we will examine the role of EGR1 in the transdifferentiation of CBs. Functional assays such as ChIP will be used to analyze the regulation of EGR1 on TWIST1 and the mutual regulation of TWIST1 and Sox9. Finally, we will examine whether this pathway play an important role in MMV by using clinical tissue specimens and animal models. Through this study, we will try to clarify the mechanism of transdifferentiation from VICs to CBs, and provide a target for the prevention and treatment of MMV.