肠道成纤维细胞是引起克罗恩病（CD）肠道纤维化的主要效应细胞，其活化机制仍不明确。研究表明转录因子HHEX参与了肠道炎症反应，但HHEX在CD肠道纤维化中的作用尚未阐明。课题组前期研究发现：HHEX在CD肠道狭窄段及其来源的原代成纤维细胞中表达上调，对成纤维细胞的活化具有正向调控作用；RNA-seq结果提示HHEX与Hippo通路关系密切，进一步发现YAP启动子区存在多节段与HHEX结合，提示YAP是HHEX的直接下游靶基因，受HHEX的转录调控。据此我们提出假说：HHEX通过与YAP启动子区结合，形成HHEX-YAP转录调控轴，使成纤维细胞活化，从而促进了CD肠道纤维化。本研究拟通过体内构建基因敲除小鼠慢性肠炎模型、体外细胞功能与分子机制实验，结合临床组织验证，深入探讨HHEX-YAP转录调控轴促进肠道纤维化的功能和分子机制，旨在为CD肠道纤维化的靶向治疗和机制研究提供新的理论依据。

Intestinal fibroblast is the main effector cell causing intestinal fibrosis in crohn’s disease (CD), but the mechanism of its activation is still unclear. Previous studies have indicated that transcription factor HHEX was involved in the intestinal inflammatory response. However, the role of HHEX in intestinal fibrosis in CD has not been elucidated. In our previous studies, we found that the transcription factor HHEX was up-regulated in the intestinal stenosis of CD patients and primary cultured fibroblasts derived from the colon with stenosis, with a positive regulatory effect on fibroblast activation. RNA-seq results suggested that HHEX was closely related to the Hippo signaling pathway. We further found that multiple segments of YAP promoter region can bind to HHEX, indicating that YAP is a direct downstream target gene of HHEX. Accordingly, we proposed the hypothesis that HHEX could directly activate YAP expression by binding to the YAP promoter region to form the HHEX-YAP transcriptional regulatory axis, thus promoting the activation of fibroblast and then facilitating the progress of intestinal fibrosis in CD. This project is intended to clarify the function and molecular mechanism of HHEX-YAP transcriptional regulatory axis in intestinal fibrosis by constructing the knockout mice model, functional and mechanism experiments in vitro and analysis in clinical CD specimens, aiming to provide further theoretical evidence and experimental foundation for treatment and mechanism research of intestinal fibrosis in CD.