基于Nrf2介导的HMGB1/β-catenin途径探讨玉屏风散总苷在上皮间质转化中的调控机制

项目名称： 基于Nrf2介导的HMGB1/β-catenin途径探讨玉屏风散总苷在上皮间质转化中的调控机制

项目编号： No.81503330

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 许亮

作者单位： 安徽医科大学

项目金额： 18万元

中文摘要： 肺纤维化（PF）危害严重，发病机制未明，缺乏有效的治疗手段。Nrf2是氧化应激中起保护性作用的转录因子，在肺纤维化中起关键调节作用。HMGB1以及β-catenin通路在上皮间质转化（EMT）中均发挥重要作用。但Nrf2与HMGB1及β-catenin通路在EMT进程中的关系如何，迄今国内外尚未见报道。前期研究发现，玉屏风总苷（YTG）通过下调HMGB1抗肺纤维化，体外抑制β-catenin通路可降低HMGB1的表达；大鼠PF模型中Nrf2的表达上调，细胞水平Nrf2沉默后，纤维化程度增加。结合文献和既往研究基础，我们推测Nrf2可能通过HMGB1/β-catenin通路加剧PF进程。为验证假说，本项目拟在Nrf2基因敲除小鼠和细胞PF模型上，探讨Nrf2对HMGB1及β-catenin的调控机制和YTG的干预作用，以寻求PF的新靶点和新药物，为中医药防治PF提供新思路。

中文关键词： 肺纤维化；上皮间质转化；HMGB1；β-catenin通路；玉屏风散总苷

英文摘要： Pulmonary fibrosis (PF) is a serious lung disease with the unknown pathogenesis and lacks of effective treatment and drugs. Nrf2 is a protective transcription factor of oxidative stress, which plays an important role in regulating PF progression. It was found out that HMGB1 and β-catenin pathway are closely related to epithelial-mesenchymal transformation (EMT) in PF. However, there has rarely about the relationship among Nrf2, HMGB1 and β-catenin pathway in regulating EMT so far. Previous studies have found that total glycosides of Yupingfeng (YTG) is capable of anti-PF action through down-regulation of HMGB1, and inhibition of β-catenin can also reduce the expression of HMGB1 in vitro. Moreover, the expression of Nrf2 is up-regulated in PF model, and the inhibition of Nrf2 could increase the degree of PF. Here, we hypothesize that Nrf2 could intensify the process of PF through HMGB1 /β-catenin pathway. To verify this hypothesis, we intend to explore the expression of HMGB1 and β-catenin in Nrf2-/- and Nrf2+/+ PF model, discuss the regulation mechanism of Nrf2 and the intervention effect of YTG, find the new targets and drugs for PF, and provide new ideas for PF treatment with TCM.

英文关键词： pulmonary fibrosis;epithelial-mesenchymal transition;HMGB1;β-catenin pathway;total glycosides of Yupingfengsan