Smad7在皮肤纤维化发生中的作用及靶分子的鉴定

项目名称： Smad7在皮肤纤维化发生中的作用及靶分子的鉴定

项目编号： No.81472903

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： 韩钢文

作者单位： 北京大学

项目金额： 70万元

中文摘要： 皮肤纤维化如硬皮病及瘢痕疙瘩是危害人类身心健康的一类常见疾病，目前缺乏有效疗法。TGF-β及Wnt信号通路的异常活化与组织纤维化的发生密切相关。Smad7作为TGF-β信号通路的重要抑制因子，在皮肤纤维化组织中表达下调。动物实验提示表皮细胞Smad7可促进β-catenin的降解而抑制Wnt信号通路、并通过表皮-真皮相互作用而抑制创伤愈合时纤维细胞胶原蛋白的表达，因而我们推测皮肤表皮细胞和纤维细胞Smad7可能通过不同的靶基因或机制发生抗纤维化作用。为证实这一设想，本申请拟应用条件型基因敲除动物分别解析表皮细胞及纤维细胞源性Smad7在纤维化发生中的作用，进一步以Smad7转基因或基因敲出的表皮或纤维细胞为材料，应用高通量基因测序技术、免疫学及分子生物学方法筛选鉴定介导Smad7抗纤维化的靶基因及其临床意义。研究结果将推进皮肤纤维化作用机制的研究并可能提供治疗纤维化疾病的潜在新靶点。

中文关键词： 动物模型；皮肤纤维化；高通量测序；信号通路；Smad7

英文摘要： Cutaneous fibrosis including scleroderma and keloid is common and detrimental disease as lacking of efficient therapy. Activation of TGF-β and Wnt signaling pathway mainly contribute to the pathogenesis of fibrosis. As an antagonist of TGF-β signaling, Smad7 has reduced expression in cutaneous fibrotic diseases. Studies from animal model have suggested that overexpression of Smad7 in epidermis promote degradation of β-catenin and also inhibits expression of collagen by fibroblasts during wound healing through epidermal-dermal interaction. We hypothesize that Smad7 from both keratinocytes and fibroblasts may play anti-fibrotic role in different mechanism or using different targets. In current application, we propose to evaluate the role of endogenous epidermal and fibroblast Smad7 in the pathogenesis of cutaneous fibrosis. Furthermore, high throughput sequencing will be performed to screen Smad7 target genes using different Smad7 transgenic or knockout cells. For top competitive Smad7 target genes, we will perform immunologic and molecular analysis to determine their association with Smad7 and also validate their clinical significance in human cutaneous fibrotic diseases. The study will advance our current understanding for the mechanism of cutaneous fibrosis and might provide novel potential targets for treating skin fibrosis.

英文关键词： animal model;cutaneous fibrosis;high-throughput sequencing;signal pathway;Smad7