HMGB1/RAGE轴通过破坏气道上皮生物钟核心元件BMAL1稳定性促进TDI哮喘气道炎症

The airway inflammation and clinical symptoms of asthma show the character of circadian rhythm.The dysfunction of circadian rhythms is closely relevant to the inflammation，remodeling and hyperreactivity of airway, but the mechanism of its involvement in asthma is still unclear. Our group members have found that the HMGB1/RAGE axis played an important role in the airway inflammation in toluene diisocyanate(TDI)-induced ashma.The biological clock genes ,such as BMAL1, NPAS2, PER1, PER2, PER3 and NR1D1, show the abnormal expression in the further research on gene chip. Western Blot found TDI could inhibit the expression of BMAL1, one of the core clock proteins, but it could be moderated through blocking RAGE. Therefore, we hypothesis that HMGB1/RAGE axis took part in the process of TDI-induced airway inflammation in ashima by damaging the stability of BMAL1 in airway epithelium. The project plans to build the TDI-induced ashima model and airway epithelium model by the way of inhibitor,gene knockout,and gene mutation, aiming to explore the mechanim of HMGB1/RAGE axis promoting TDI-induced airway inflammation by damaging the stability of BMAL1 in airway epithelium, which could provide the new evidence of asthmatic therapy.

哮喘气道炎症及临床症状具有昼夜节律特点，生物钟功能障碍与气道炎症、气道重塑、气道高反应性密切相关，然而其参与哮喘的机制尚不清楚。本课题组发现HMGB1/RAGE轴在TDI哮喘气道炎症中发挥重要作用，进一步基因芯片发现TDI哮喘小鼠生物钟基因（BMAL1、NPAS2、PER1、PER2、PER3和NR1D1）表达异常；Western Blot发现TDI可抑制生物钟核心元件BMAL1表达，阻断RAGE可缓解该过程。体外发现HMGB1可抑制气道上皮细胞BMAL1表达，这同样受RAGE的影响。因此提出科学假说：“HMGB1/RAGE轴通过破坏气道上皮BMAL1的稳定性参与TDI哮喘气道炎症”。本项目拟采用TDI哮喘模型和气道上皮细胞模型，通过抑制剂、基因敲除及突变等方法，探讨HMGB1/RAGE轴通过破坏气道上皮BMAL1稳定性促进TDI哮喘气道炎症的分子机制，为哮喘防治提供新的理论依据。

哮喘气道炎症及临床症状具有昼夜节律特点，生物钟功能障碍与气道炎症、气道重塑、气道高反应性密切相关，然而其参与哮喘的机制尚不清楚。本项目重点探讨HMGB1/RAGE轴通过破坏气道上皮BMAL1稳定性促进TDI哮喘气道炎症的分子机制，为哮喘防治提供新的理论依据。重要结果及关键数据：（1）首次在TDI哮喘模型中发现Rage可以通过BMAL1参与哮喘气道炎症；（2）首次发现在TDI哮喘模型中，RAGE通过PI3K/AKT通路调节HDAC1的表达，并且发现抑制HDAC可改善TDI诱导的气道炎症及气道屏障功能；（3）首次发现抑制TAK1可能通过增加RIPK1的活性，引起Caspase 8的持续活化而增加巨噬细胞的死亡，参与促进TDI诱导的哮喘小鼠气道炎症。在该课题研究期间，发表论文5篇，其中SCI论文1篇，中文核心4篇；协助培养博士研究生1名，硕士研究生5名；积极参与国内、国际学术会议交流。