风湿性心脏瓣膜病（RVD），是一种继发于风湿性心脏病（RHD）的瓣膜疾病。内皮间充质转化(EndMT)在多种疾病中发挥关键作用，但其在RVD中的作用及机制尚不明确。我们前期研究发现，Lewis大鼠RHD模型中与EndMT过程相关的Activin/Smad2、3信号激活，且伴随多种EndMT标志性蛋白（α志性蛋白、COL18A1、periostin）表达水平增高。因此我们推测，Actinin/Smad2、3信号通路可通过调控EndMT过程介导RHD进展。本课题拟采用RHD患者来源的多能诱导干细胞定向分化的内皮细胞、构建Lewis大鼠RHD模型，并结合CRISPR/Cas9基因编辑、流式分选、高内涵分析系统等技术，阐明Activin/Smad2、3调控RHD内皮间充质转化并导致二尖瓣功能障碍的机制，以阐述RHD的病理发生机制，为RHD的防治提供新思路和干预靶点。

Rheumatic valvular disease (RVD) is a valvular disease secondary to rheumatic heart disease (RHD). Studies have found that EndMT plays a key role in a variety of endothelium-related diseases, but its specific role and mechanism in RVD is still not clear. Our previous study found that the Activin/Smad2,3 signaling pathway is activated which is associated with the EndMT process in the Lewis rat RHD model. Meanwhile, the expression of several EndMT protein markers(α-SMA,COL18A1, periostin) was significantly increased. Therefore, we hypothesized that the Activin/Smad2,3 signaling pathway may mediate the progression of RHD by regulating EndMT. Therefore, we in vitro establish the endothelial cells differentiated from iPSCs lineages which is induced from somatic cells of RHD patients, and in vivo establish Lewis rat RHD models, by using CRISPR/Cas9 gene editing, fluorescence activated cell sorting, and widefield high content screening system, to elucidate the specific role of activin/Smad2,3 signaling pathways in regulating the EndMT and leading to mitral valve dysfunction. This work will provide a new theory of pathological mechanism of RHD, and give a new insight into the prevention and treatment against RHD.