FSTL1通过DIP2A受体诱导气道上皮细胞自噬促进哮喘气道重塑机制研究

气道重塑是导致哮喘患者肺功能下降及固定性气流受限，进而劳动力丧失、生活质量下降的主要原因。我们前期研究发现，FSTL1在哮喘患者外周血及肺泡灌洗液中高表达， FSTL1也高表达于气道上皮，并伴随自噬小体及重塑标记物纤维连接蛋白和α–SMA的高表达。以上结果提示FSTL1及细胞自噬在气道重塑中可能发挥重要作用。本研究拟通过FSTL1基因敲除小鼠模型及体外气道上皮和成纤维细胞培养的试验方法，探讨FSTL1诱导气道上皮细胞自噬促进气道重塑的机制，证实如下假说：FSTL1与DIP2A受体结合，激活上皮细胞自噬，介导上皮细胞间质转化（间质标记物N-cadherin、vimentin高表达）及成纤维细胞内MAPK信号通路的活化，促进重塑标记物高表达，最终导致气道重塑的发生。本研究以FSTL1和细胞自噬为切入点，旨在阐明其导致气道重塑的具体机制，为早期防治哮喘病人固定性气流受限提供临床治疗思路。

Asthma is a chronic disease featured by airway hyperresponsiveness and airway remodeling. Airway remodeling is the important reason of refractory asthma. Our previous studies have shown that the level of Follistatin-like protein 1 （FSTL1）in peripheral blood and bronchocalveolar lavage fluid (BALF) was increased compared to healthy controls. Meanwhile, FSTL1 was overexpressed accompanied by increased autophagosome and asthmatic airway remodeling markers including α -smooth muscle actin (α -SMA) and collagen I. Therefore, we suggested FSTL1 and autophagy may play a critical role in airway remodeling in asthma. According to the preliminary research data, we intended to detect the mechanism of FSTL1-induced airway remodeling by intensifying autophagy from various levels of organ, cell and molecules. In this research, we intend to use Fstl1+/- mouse to explore the role of FSTL1 in autophagy and asthma remodeling. In addation, the mechanism and signaling pathway of FSTL1-induced airway remodeling will be detected by culturing human bronchial epithelial cells and lung fibroblast line in vitro. We design to confirm the overexpression of FSTL1 binding to DIP2A on airway epithelial cells and intensifying autophagy in epithelia, and then activating MAPKs or Smad signal pathway in fibroblast followed by the deposition of N-cadherin,vimentin, fibronectin, collagen I and α -SMA. In this study, we will focus on the mechanism of FSTL1-induced airway remodeling and look for the effective intervention targets. This research could provide novel avenues for theoretical basis of airway remodeling to preventing asthma patients from fixed airflow limitation, and develope a new therapeutic strategy for asthma.