TGF-β1与TWEAK信号通路交叉对话在哮喘气道重塑中的作用及隐丹参酮的干预机制研究

气道平滑肌细胞(ASMCs)增殖是哮喘气道重塑发生、发展的关键环节。研究表明，TGF-β1和TWEAK信号通路在下游STAT3进行交叉。我们的前期研究发现：TWEAK干预ASMCs培养上清液和细胞内TGF-β1 的水平明显增高，ASMCs增殖与TGF-β1 呈正相关；而且隐丹参酮通过减少TGF-β1和TWEAK蛋白的表达，明显抑制气道重塑的演进。但上述信号通路交叉与气道重塑以及隐丹参酮干预的相关机制尚不清楚。本课题拟通过ASMCs和哮喘气道重塑模型，从分子、细胞和整体水平，探讨TGF-β1和TWEAK激动剂、抑制剂以及隐丹参酮对TGF-β1、TWEAK信号通路及靶基因的影响，阐明TGF-β1和TWEAK 信号通路交叉对话在哮喘气道重塑中的作用，明确隐丹参酮介导TGF-β1和TWEAK 信号通路交叉改善气道重塑的作用机制。为寻找防治哮喘气道重塑及新药开发提供有效的理论依据。

Airway smooth muscle cells (ASMCs) proliferation is well-known to be a major factor in asthmatic airway remodeling. It has been reported that STAT3 was an intersection point under TGF-β1 and TWEAK signaling pathway downstream in previous research. Our previous study showed TGF-β1 expression increasing in ASMCs and culture supernatant treatment with TWEAK had positive correlation with ASMCs proliferation. In addition, Cryptotanshinone inhibited the proteins expression of TGF-β1 and TWEAK to play a significant inhibitory effect on airway remodeling. In all of the research detailed evaluation of the effects of cross-talk above and cryptotanshinone on airway remodeling is still missing. Here we use ASMCs and airway remodeling model mice to investigate the effects of agonist and inhibitor of TGF-β1 and TWEAK and cryptotanshinone on TGF-β1 & TWEAK signaling pathway and target gene, and elucidate the effect of the cross-talk between TGF-β1 and TWEAK signaling pathway on airway remodeling. Furthermore, we will clarify the underlying mechanism of cryptotanshinone on mediating the molecular cross-talk between TGF-β1 and TWEAK signal transduction. This study will obtain the effective theoretical basis for prevention or treatment of airway remodeling in asthma and the development of new drugs.