Six1通过TGF-β/Smad信号通路诱导上皮细胞EMT促进哮喘小鼠气道重塑的机制研究

Airway remodeling is a major character of asthma, which is the main reason of persistent airway hyperresponsiveness and irreversible airway obstruction, but the mechanism remains unclear. Our previous research has already demonstrated that bronchial epithelial cells transform into mesenchymal cells play an important role in airway remodeling. Our cDNA microarray and immunohistochemistry results validated the significantly higher expressions of Six1 in asthmatic mice, which significantly associated with α-SMA and E-cadherin expression. Silencing of Six1 inhibits airway remodeling and hyperresponsiveness, as well as suppresses TGF-β/Smad signaling pathway activity in an OVA-induced model of asthma. On the basis of our preliminary results, we plan to further study the role of Six1 on regulation of cell phenotype in bronchial epithelial cells both in vitro and in vivo. In addition, the molecule mechanism of Six1 on regulation of TGF-β/Smad signal pathway will be investigated. After that, we will screen and test the potential upstream regulators and downstream targets of Six1 in asthmatic mice. The results of the present study will be valuable for future investigations of effective prevention and treatment of airway remodeling in asthma, and provide cues and information for studying the mechanisms of pulmonary fibrosis.

气道重塑是哮喘病的重要病理改变，亦是引起通气功能障碍和气道高反应性的主要原因，但其分子机制尚不明确。我们前期研究发现支气管上皮细胞成纤维转化在气道重塑中发挥重要作用，实验发现Six1在哮喘模型组高表达且与EMT特征密切相关；靶向阻断Six1后哮喘组小鼠气道重塑受到明显抑制，气道高反应性得到有效控制，同时基因芯片筛选显示TGF-β/Smad信号通路受到明显抑制。本课题在此基础上拟从分子、细胞、动物层面研究Six1对上皮细胞EMT表型的调控作用及对气道重塑的影响，通过构建体内外哮喘模型分析Six1对TGF-β/Smad通路的调节作用和分子机制，利用生物信息学等手段寻找可能与Six1相互作用的蛋白质，进而筛选并验证Six1的上游调节因子和下游作用靶点，揭示Six1发挥生物学功能涉及的分子机制。研究结果将明确Six1在哮喘中的作用和具体机制，为有效防治哮喘气道重塑提供新的分子靶点和理论依据。

支气管哮喘是常见的呼吸道慢性疾病之一，其发病率在全球范围内呈增加的趋势，成为严重危害人类健康的公共健康问题。气道重塑是哮喘患者肺功能损伤的病理基础，也是哮喘症状反复发作的重要原因，但其分子机制尚不明确。我们在分子、细胞、动物、人体等层面深入揭示气道重塑的重要诱导因子和调控机制，研究发现：1.Six1是诱导哮喘气道重塑的重要因子。2.Six1通过TGF-β1/Smad信号通路促进哮喘EMT间质转化及气道纤维化。3.miR-448-5p是Six1的上游调控因子，二者具有负向调控关系，miR-448-5p可能通过靶向调控Six1抑制TGF-β1诱导的支气管上皮细胞EMT间充质转化和气道纤维化。课题组首次系统研究了Six1与哮喘气道重塑的关系及其作用机制，为哮喘气道重塑机制研究提供了新的分子靶点，为哮喘分子治疗提供理论依据。