FLG突变对中间丝相关蛋白表达和皮肤屏障功能的影响

项目名称： FLG突变对中间丝相关蛋白表达和皮肤屏障功能的影响

项目编号： No.81201227

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 张卉

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 2006年，研究发现中间丝相关蛋白基因（FLG）无义突变与特应性皮炎（AD）相关；此后，多个研究小组在不同人群对FLG的结构特征及其突变与AD发病的关系进行了大量的研究；但这些研究没有涉及突变位点的不同与基因表达产物和皮肤屏障功能的关系。前期研究中我们通过对中国人群AD进行FLG全基因测序，明确FLG突变与中国人群AD发病强相关，并且首次发现了17个新突变，将文献报道的FLG突变数目增加到45种以上。那么不同突变位点对中间丝相关蛋白的表达和皮肤屏障功能的影响是否不同？本研究的目的拟利用基因克隆技术，构建角质形成细胞FLG突变株，使定点突变在角质形成细胞上稳定表达；而后利用已成熟应用于皮肤移植领域的器官特征性皮肤培养使突变细胞株模拟人体表皮各层分化结构，从器官水平研究FLG突变对中间丝相关蛋白表达和皮肤屏障功能的影响。

中文关键词： 特应性皮炎；中间丝相关蛋白基因；穿心莲内酯；随访研究；多态性

英文摘要： In 2006, loss-of-function mutations in the filaggrin gene were demonstrated to be associated with atopic dermatitis for the first time. Subsequently multiple studies have been done in various populations mainly on the structure of FLG gene and its relationship with atopic dermatitis, however, rarely covering the relationship of the expression of filaggrin caused by various mutation sites in the FLG gene and epithelial barrier function.We previously carried out a comprehensive sequencing of the entire FLG coding region in 600 Han AD patients and confirmed the relationship of FLG mutations with atopic dermatitis. Over 45 types of FLG mutations have been identified including 17 new FLG mutations discovered in our study. The effect of various FLG mutations on the expression of filaggrin and epithelial barrier function remains unclear. The current study is focused on the effect of different FLG mutations on the expression of filaggrin and epithelial barrier fuction from oganic levels: Stable expression of filaggrin with site-directed mutagenesis followed by FLG-mutant composition in keritinocytes by gene-cloning technique is to be constructed. Organotypic skin cultures, which have been maturely implemented in skin-grafting area, will be performed on FLG-mutant imitating epidermis differentiation in vivo.

英文关键词： Atopic dermatitis；Filaggrin gene；Andrographolide；Follow-up study；Polymorphism