靶向XBP1新结构激动剂筛选及抗溃疡性结肠炎作用机制研究

项目名称： 靶向XBP1新结构激动剂筛选及抗溃疡性结肠炎作用机制研究

项目编号： No.81202546

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 吴练秋

作者单位： 中国医学科学院药物研究所

项目金额： 23万元

中文摘要： 溃疡性结肠炎(Ulcerative colitis，UC)是一种迁延发作、难于根治、易伴发恶变的肠道疾病，目前临床上缺乏有效的治疗药物及方法。X box binding protein 1 (XBP1)是肠上皮细胞内与内质网应激相关的关键性核转录因子。新近临床遗传学到实验室研究证据均表明：XBP1的表达下调或缺失会促进UC的发生及发展。但目前国内外有关UC药物研发中以XBP1作为靶标的药物尚无报道。本项目前期已建立靶向XBP1体外高通量药物筛选模型和体内急、慢性UC实验动物模型，并对推测具有抗肠道炎症的系列新结构化合物展开初筛。初步发现一类新结构化合物具有显著的XBP1转录激活效应，其中化合物ZZH-128体内活性较好，并呈现良好的量效关系。本研究拟进一步进行XBP1激动剂的筛选，并对体内外均具有较高活性的化合物进行详尽的分子作用机制研究，从而为创制分子靶向XBP1的抗UC药物研究奠定基础

中文关键词： 溃疡性结肠炎；激动剂；XBP1；NF-κB；转录调控

英文摘要： Ulcerative colitis (UC) is a chronic disease with refractory character, and occasionally convert to malignant intestinal disorder. At present, the effective clinical treatment is lacking for UC. X box binding protein 1 (XBP1) is the key nuclear transcription factor in the intestinal epithelial cells related with endoplasmic reticulum stress. Recently, evidences from clinical genetics and laboratory research were found that XBP1 down-expression or deletion can promote the occurrence and development of UC. Moreover, higher expression of XBP1 can be against the intestinal epithelial cell apoptosis induced by uncontrolled endoplasmic reticulum stress. However, there were no reports about XBP1 as a drug target in the research and development of UC therapeutic medicine. This project has established high-throughput drug screening model targeting XBP1 in vitro and acute or chronic UC experimental animal models in vivo, and started to screen series of new structure compounds which were presumed to have potential anti-inflammatory activity. The primary study showed that a class of compounds has significant XBP1 transcriptional activated effect, wherein ZZH-128 has higher anti-inflammatory activity dose-dependently in vitro and vivo. This study try to find more XBP1 agonists by screening, and to explore the detailed molecu

英文关键词： ulcerative colitis；agonist；XBP1；NF-κB；transcriptional regulation