DOPEY1-TRIP12-p53信号轴在幽门螺杆菌感染致病中的作用及其机制研究

P53被认为是机体最重要的“基因卫士”之一，参与阻滞细胞周期进展及促进细胞凋亡等过程。幽门螺杆菌（Hp）感染可诱导p53突变导致其活性降低，促进胃黏膜疾病进展，但此过程的监管机制尚未完全阐明。我们前期研究通过转录组学数据及细胞、动物模型证实Hp感染上调DOPEY家族成员1（DOPEY1）的表达。进一步通过生物信息学分析发现DOPEY1与泛素连接酶TRIP12相互作用且两者表达呈正相关关系，而后者通过HDM2调控p53的表达。干扰DOPEY1后可下调p-HDM2的表达进而增强p53的活性。据此，我们推测Hp感染可上调DOPEY1的表达，通过TRIP12-HDM2导致p53活性降低，细胞增殖/凋亡失衡，导致胃黏膜疾病的发生。本课题拟通过体内外实验系统研究DOPEY1-TRIP12-p53信号轴在Hp感染致病中的作用及分子机制，为Hp相关胃黏膜疾病的预防提供新的治疗靶点。

P53 is one of the most important “guardian of the genome integrity”, which involved in the processes of cell cycle arrest and cell apoptosis. Helicobacter pylori (H. pylori) infection induces the mutation of p53, leading to the decreased activity of p53, which then promotes the progression of gastric mucosa. However, the regulation mechanism underlying this process remains unclear. Our previous study found that dopey family member 1 (DOPEY1) was increased by H. pylori infection by analysis of the transcriptome data and using cell and mice model. In addition, bioinformatic analysis revealed that DOPEY1 interacted with E3 ubiquitin ligase TRIP12 (involved in the regulation of p53 through HDM2), and their expression was positively correlated. Knocking down DOPEY1 could downregulate the p-HDM2 expression, leading to the increased activity of p53. Therefore, we hypothesized that H. pylori infection leads to the reduction of p53 activity via upregulation of expression of DOPEY1 and subsequent TRIP12-HDM2. These H. pylori-induced cellular events deregulates the balance of cell growth and apoptosis, which contributes to the incidence of gastric diseases. Our proposal aims to mechanistically dissect the role of the DOPEY1-TRIP12-p53 signaling axis during the pathogenesis of H. pylori infection, which could potentially identify the novel target for the treatment and prevention of H. pylori-associated diseases.