RUNX1调控的FMT在宫腔粘连发生中的机制研究

宫腔粘连是子宫内膜上皮细胞受损后再生修复障碍所引起的局部纤维化疾病，严重影响了女性生殖健康。成纤维细胞向肌成纤维细胞转分化（FMT）是维持细胞外基质稳态的重要环节之一，其过度激活会导致纤维化发生。近年研究发现RUNX1在多种组织纤维化中表达异常，但是否参与了宫腔粘连尚未见报道。申请人前期通过单细胞测序分析发现RUNX1为FMT进程中的潜在调控子；在宫腔粘连临床及动物样本中高表达；敲低RUNX1能降低TGF-β1诱导的FMT和纤维化标志物以及PI3K亚基p110δ和p-Akt的表达；ChIP实验表明RUNX1能结合PI3KCD启动子区。据此推测：RUNX1通过活化PI3K/Akt激活TGF-β1诱导的FMT，促进了宫腔粘连纤维化的形成。本研究拟通过单细胞测序、蛋白和RNA分析，基于临床样本、动物和细胞模型探讨RUNX1在宫腔粘连纤维化中的作用和机制，以期为相关的治疗靶点和药物提供坚实的依据。

Intrauterine adhesion (IUA) was a fibrotic disease caused by the failure of regeneration and repair in endometrial epithelial cells, which seriously affects women's reproductive health. Fibroblast-to-Myofibroblast transdifferentiation (FMT) was one of the most important process in maintaining extracellular matrix homeostasis and its excessive activation could lead to fibrosis. Recently, many studies found runt-related transcription factor 1(RUNX1) was abnormally expressed in various tissue fibrosis. However, the function of RUNX1 in IUA has not been reported. I previously identified RUNX1 as a potential regulator in FMT by using single cell sequencing analysis. Meanwhile, I found that RUNX1 was up-regulated in clinical and animal sample. Knockdown of RUNX1 could reduce TGF-β1-induced FMT and expression of fibrosis markers, PI3K subunits p110δ and p-Akt. ChIP experiments showed that RUNX1 could bind to the PI3KCD promoter region. Given the above results, I propose that RUNX1 promotes TGF-β1-Induced Fibroblast-to-Myofibroblast (FMT) and IUA fibrosis through the PI3K/Akt. Here, we will use molecular biology techniques including single cell sequencing to explore RUNX1-mediated activation of TGF-β1-Induced FMT and its role in IUA fibrosis by using our developed mouse model. The findings of this proposal will provide novel insight into not only the underlying mechanism of fibrosis in IUA but also for the development of novel agents for treating IUA.