上皮特异性转录因子BNC1在慢性鼻窦炎上皮间质样转化中的分子机制研究

Nasal epithelial structure and function disorders (tissue remodeling) is one of the core pathological features of the development of chronic rhinosinusitis (CRS), while epithelial-to-mesenchymal transition (EMT)is the key point of tissue remodeling. The applicant carried out pooling based Genome wide association study and found a significantly association between basonuclin1 (BNC1) gene polymorphisms and CRS with funding from National Science Fund. Moreover, is was demonstrated that BNC1 expressed in the whole layer of sinus mucosa epithelium in CRS subjects and exhibited a significantly higher mRNA level compared with healthy control nasal mucosa. In addition, it has been proofed that BNC1 may play a role in the occurrence of CRS through influencing sinus mucosa function. The aim of present study is to investigate the interior relation between BNC1 expression changes and EMT degree of the sinus epithelium in patients suffering from CRS through three aspects which include tissue, cell and animal to reveal the potential mechanisms of BNC1 in the nasal epithelial EMT process mediated by transforming growth factor beta1 / smad3 pathway. The research will help to elucidate the molecular mechanisms of epithelial remodeling of CRS and provide new molecular targets and new ideas regarding the prevention and treatment of CRS.

鼻粘膜上皮结构及功能紊乱(组织重塑)是慢性鼻窦炎(chronic rhinosinusitis,CRS)发病的核心病理特征之一，上皮间质样转化(epithelial-to-mesenchymal transition, EMT)是上皮组织重塑的关键环节。申请人前期在国自然项目的资助下，开展全基因组关联研究发现位于碱性核蛋白1(basonuclin1, BNC1)基因的多态性与CRS发生相关，BNC1在CRS鼻窦粘膜上皮全层表达，且较正常粘膜表达增高，BNC1可能通过影响鼻窦粘膜上皮功能在CRS发生中发挥作用。本课题拟从组织-细胞-动物三个层次深入研究，探讨CRS上皮EMT程度与BNC1表达变化的内在联系，并揭示BNC1在转化生长因子beta1/smad3通路介导的鼻粘膜上皮EMT过程的具体分子机制。本研究将有助于深入阐明CRS上皮重塑的分子机制，为CRS的防治提供新的分子靶标和新思路。

鼻粘膜上皮结构及功能紊乱(组织重塑)是慢性鼻窦炎（chronic rhinosinusitis，CRS）发病的核心病理特征之一，上皮间质样转化(epithelial-to-mesenchymal transition, EMT)是上皮组织重塑的关键环节。前期全基因组样本汇聚研究发现位于碱性核蛋白1(basonuclin1, BNC1)基因的多态性与CRS发生相关，BNC1在CRS鼻窦粘膜上皮全层表达，且较正常粘膜表达增高，BNC1可能通过影响鼻窦粘膜上皮功能在CRS发生中发挥作用。研究募集了32例CRS伴鼻息肉(CRSwNP)患者、22例CRS不伴鼻息肉(CRSsNP)患者和13例正常对照受试者鼻黏膜组织标本，研究结果发现CRSwNP患者鼻粘膜组织中BNC1表达明显高于正常对照组和CRSsNP，同时伴有EMT相关表型蛋白的改变。体外细胞培养实验发现BNC1和EMT均受到TGF-β1/smad3通路的调控，TGF-β1刺激可增高BNC1表达，并促进EMT。双荧光素酶报告基因实验及免疫染色质共沉淀实验表明可能存在其他因素影响TGF-β1/smad3对BNC1的调控。研究中发现BNC1表达与增殖相关基因P63表达存在高度相关性，提示BNC1可能参与上皮细胞增殖过程，这是我们下一步研究需要调整和验证的方向。项目在研期间共发表英文文章15篇，中文核心期刊文章6篇，获批国家级科研项目1项，省级科研项目4项，以主要完成人获得科研奖励3项。申请人2次受邀国际学术会议发言、4次受邀国内中华医学会学术会议发言。