MRN复合物介导炎症信号的机制研究及其在慢性气道炎症中的病理作用

Asthma and chronic obstructive pulmonary disease (COPD) are the most common chronic airway inflammatory diseases. Recent studies have demonstrated that oxidative stress was 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. MRN complex is a sensor of DSBs that also controls the DDR by governing the activation of the central transducing kinase ATM. It has been reported that the MRE11–RAD50 complex plays important roles in recognition of dsDNA and initiation of STING-dependent signaling, in addition to its role in DNA-damage response. In our previous study, we found that the MRN complex is also involved in chronic airway inflammation， inhibiting MRN complex will attenuate the airway inflammation in an animal model. In this project, we will trying to explore the roles of MRN complex in inflammatory signaling during the chronic airway inflammation and to determine the possibilities of utilizing MRN complex inhibitors as the treatment for chronic airway inflammation therapies.

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，近来研究发现氧化DNA损伤参与了哮喘和COPD发病的病理过程，介导了炎症反应过程，可能是激素不敏感的重要分子机制之一。MRN复合物是DNA损伤修复通路中的关键蛋白复合物，已有研究发现MRN复合物除调控DNA损伤修复反应之外，还能够介导由DNA损伤副产物引发的炎症反应过程。已有关于MRN复合物介导炎症反应的研究多集中于病原体感染过程，我们前期研究发现，MRN复合物介导的炎症反应还参与了慢性气道炎症病理生理过程,抑制MRN复合物活性可以缓解慢性气道炎症。本项目将研究在慢性气道炎症上皮细胞DNA损伤过程中MRN复合物是否介导了炎症反应的产生，并揭示具体的分子机制；阐明MRN复合物介导的上皮细胞炎症反应调控气道炎症的病理机制；探索在慢性气道炎症中以MRN复合物为潜在治疗靶点，为慢性气道炎症的靶向治疗研究提供实验依据。

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，近来研究发现氧化DNA损伤参与了哮喘和COPD发病的病理过程，介导炎症反应过程。MRN复合物是DNA损伤修复中的关键复合物，参与介导由DNA损伤副产物引发的炎症反应过程。本项目研究了慢性气道炎症过程中上皮细胞DNA损伤修复反应的调控作用，发现MRN复合物蛋白RAD50参与调控小鼠慢性气道炎症。发现MRN复合物抑制剂可缓解过敏原诱导的上皮细胞炎症，同时拓展研究发现，RAD50敲除还参与调控LPS诱导的小鼠气道炎症。综上，本项目研究为慢性气道炎症的靶向治疗研究提供了潜在新靶点。