应用体外细胞模型和斑马鱼在体模型探讨RNASET2介导黑素细胞凋亡的分子机制研究

项目名称： 应用体外细胞模型和斑马鱼在体模型探讨RNASET2介导黑素细胞凋亡的分子机制研究

项目编号： No.81472901

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 项蕾红

作者单位： 复旦大学

项目金额： 80万元

中文摘要： 遗传因素在白癜风发病中起着重要作用，2010年我们通过全基因组关联研究首次报道了白癜风易感基因：分泌性核酸酶RNASET2。我们前期研究发现：应激介导表皮细胞RNASET2 蛋白高表达并释放至微环境中。基于RNASET2蛋白结构中含有凋亡相关蛋白TRAF2结构域以及其可能参与免疫激活的最新文献报道，我们推断其在白癜风中发病机制：（1）RNASET2蛋白在细胞内通过与TRAF2蛋白相结合，启动凋亡通路，从而引起黑素细胞凋亡以及黑素合成减少；（2）释放至微环境中的 RNASET2与黑素细胞上特定的TLRs结合，作为 TLRs 的内源性配体参与 TLR 信号转导机制 ,诱导免疫应答，从而促使黑素细胞受到免疫攻击而破坏。因此，我们拟应用体外细胞模型和斑马鱼在体模型探讨RNASET2介导黑素细胞凋亡的分子机制，为白癜风临床治疗寻找新的靶点。

中文关键词： 黑素细胞；凋亡；分子机制；斑马鱼；分泌性核酸酶T2

英文摘要： Genetic factors play an important role in the pathogenesis of vitiligo. Our recent genome-wide association study identified a link between vitiligo and genetic variants in the ribonuclease T2 (RNASET2) gene in 2010. Our in vitro analyses indicated that overexpression of RNASET2 was inducible and released into the microenvironment in cultured primary human epidermal cells by stress conditions. Based on the latest literature that the structure of RNASET2 contained a related apoptosis TRAF2 domain and RNASET2 might be involved in immune activation.We speculate the possible pathogenesis of vitiligo : (1) RNASET2 may lead to increased cell apoptosis via the tumor necrosis factor receptor-associated factor 2 (TRAF2)-caspases pathway through the physical interaction of RNASET2 with TRAF2 by starting apoptotic pathway ;( 2 )RNASET2 released into the microenvironment may be involved in the induction of immune responses by conjuncting with the melanocyte-specific TLRs, as the endogenous ligand of TLRs signal transduction,thus contributing to immune attack . Therefore, we plan to explore the molecular mechanisms of RNASET2 in mediating apoptosis of melanocytes by application of cell model in vitro and zebrafish model in vivo and to look for new targets for the clinical treatment of vitiligo.

英文关键词： melanocyte;apoptosis;mechanism;zebrafish;RNASET2