Claudin-3：肿瘤坏死因子α调控下颌下腺紧密连接的分子靶点

项目名称： Claudin-3：肿瘤坏死因子α调控下颌下腺紧密连接的分子靶点

项目编号： No.81470756

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： 俞光岩

作者单位： 北京大学

项目金额： 73万元

中文摘要： 紧密连接是介导上皮细胞物质经旁细胞途径转运的蛋白复合体，但对其在下颌下腺中的作用了解甚少。本项目以肿瘤坏死因子α（TNF-α）诱导的下颌下腺炎症反应为主线，紧密连接蛋白claudin-3为重点，采用免疫印迹、免疫荧光、基因敲低或过表达等方法证实claudin-3在下颌下腺紧密连接中的作用；在TNF-α诱导的大鼠下颌下腺炎和SMG-C6细胞上观察紧密连接蛋白表达、分布和功能的变化，在器官、细胞和分子水平证实claudin-3是TNF-α特异性调控的紧密连接靶分子；以ERK1/2和NF-κB通路为中心，探讨TNF-α调控转录因子Egr-1和slug进而影响claudin-3表达和功能的信号转导途径。本研究将丰富紧密连接介导下颌下腺分泌的理论，揭示claudin-3在下颌下腺的生理功能，明确TNF-α调控claudin-3的分子机制，并为探讨以紧密连接为靶点防治下颌下腺炎症性疾病提供新的思路。

中文关键词： 肿瘤坏死因子α；紧密连接；claudin-3；下颌下腺；分泌

英文摘要： Tight junction is a protein complex for materials transport through paracellular route in epithelial cells; however, its exact role in submandibular gland is still unclear. Based on pro-inflammatory cytokine tumor necrosis factor-α (TNF-α)-induced inflammatory response, our present study focuses on the effect of the tight junction protein claudin-3 in submandibular gland. By using immunoblotting, immunofluorescence, gene knockdown and overexpression, we will explore the role of claudin-3 in submandibular tight junction function. On the TNF-α-induced rat submandibular inflammation and cellular model, we will detect the changes of expression, distribution and function of tight junction proteins, aiming to determine that claudin-3 is the potential target for TNF-α from both organic and cellular levels. We will further investigate the signaling pathway connecting TNF-α and claudin-3, especially focusing on ERK1/2 and NF-κB signaling pathways, together with the downstream transcriptional factors Egr-1 and slug. This study will identify the physiological and pathophysiological significance of claudin-3 in submandibular gland, explore the molecular mechanism involved in the TNF-α-regulated claudin-3, and further provide a novel insight into a future therapeutic target for inflammatory diseases of submandibular gland.

英文关键词： tumor necrosis factor α;tight junction;claudin-3;submandibular gland;secretion