ATM信号通路介导的DNA损伤应答对慢性气道炎症的调控作用

Asthma and chronic obstructive pulmonary disease (COPD) are the most common chronic airway inflammatory diseases. Recent studies have demonstrated that DNA damage response involved in the pathogenesis of asthma and COPD, and is probably one of the important molecular mechanisms of corticosteroid-insensitive in chronic airway inflammatory diseases. ATM is an important signaling pathway in DNA damge response. In our previous study, we found that inhibited of ATM reduced house dust mite and cigarette smoke-induced airway inflammation. Therefore we assume that ATM signaling pathway mediated DNA damage response may be involved in the regulation airway inflammation of asthma and COPD. In vitro study, we will use siRNA and cDNA to treat HBE cells, and primary mouse tracheal epithelial cells from ATM knockout mice, to investigate the role and mechanisams of ATM in the regulation of airways inflammation. In vivo study, well established-asthma and COPD models, as well as ATM knockout mice, will be used to investigate the role of ATM signaling pathway in chronic airway inflammation diseases. In addition, KU-60019, a small molecule inhibitor of ATM, is used to assess whether there is a protect effect in asthma and COPD. This project will hopefully provide theoretical evidence for used of DNA repair inhibitor treatment against chronic airways inflammatory diseases.

哮喘与慢性阻塞性肺疾病（COPD）是最为常见的慢性气道炎症性疾病，近来研究表明DNA损伤反应参与了哮喘和COPD的发病过程，且可能是激素不敏感的关键分子机制。已知ATM是DNA损伤应答中的一条重要通路，我们前期研究发现，抑制ATM可有效缓解屋尘螨和香烟烟雾暴露诱导的气道上皮细胞炎症反应。因此，ATM信号通路介导的DNA损伤应答可能参与了对气道炎症的调控。本项目体外研究拟利用siRNA阻断或质粒过表达ATM以及ATM基因敲除小鼠原代气道上皮细胞，以阐明ATM对气道炎症的关键调控作用及分子机制。体内研究拟利用ATM基因敲除小鼠构建哮喘和COPD模型，观察ATM在两种疾病模型中对气道炎症的调控作用。最后，利用ATM小分子抑制剂KU-60019来检测哮喘和COPD是否对阻断该信号通路敏感，为进一步开发靶向治疗药物提供新的靶点和重要实验依据。

哮喘与慢性阻塞性肺疾病（COPD）是最为常见的慢性气道炎症性疾病。气道上皮细胞DNA损伤反应参与了哮喘和COPD发病的病理、生理过程，且可能是激素不敏感的关键分子机制。本研究发现：(1)屋尘螨（HDM）及香烟烟雾暴露可诱导气道上皮细胞DNA损伤应答（DDR）及炎症反应，ATM siRNA可显著降低香烟烟雾暴露和HDM诱导的气道上皮细胞炎症反应；（2）在博莱霉素（BLM）诱导的气道上皮DDR和炎症反应中，可引起双链DNA（dsDNA）的大量释放。环GMP-AMP合成酶（Cyclic GMP-AMP synthase, cGAS）可能参与调控BLM诱导的气道上皮细胞DDR和炎症反应过程；（3）HB-EGF可促进成纤维细胞中胶原蛋白的沉积，通过诱导N-cadherin、E-cadherin及vimentin 促进气道上皮细胞的上皮细胞间质转型，引起COPD气道重塑的发生和发展，最终导致气道受限，气道中 HB-EGF 表达水平与COPD严重程度显著相关。