白芍总苷调控肥大细胞Gab2信号抗过敏哮喘机制及其配伍研究

过敏性哮喘发病率逐年上升，但缺乏有效防治药物。最新研究证明Gab2作为细胞磷酸化信号重要支架蛋白在过敏炎症信号转导中发挥了极为重要作用。我们前期发现白芍及TGP不仅能体外抑制肥大细胞脱颗粒及炎症因子释放，还能抑制体内小鼠过敏性哮喘肺泡炎症。究其机理我们初步研究发现白芍能抑制肥大细胞活化下游P-Gab2，P-Akt和P-Erk蛋白水平及Gab2/Shp2复合物形成。据此我们推测TGP通过调控Gab2信号抑制肥大细胞脱颗粒从而达到抗过敏性哮喘作用。本项目拟采用Gab转基因小鼠构建哮喘模型来明确TGP通过调控Gab2信号抗过敏哮喘药理活性；采用siRNA、iTRAQ定量蛋白质组和全转录组表达谱芯片等技术，揭示TGP对哮喘病理网络以Gab2为中心的多靶点调控；并通过谱效和协同研究探讨TGP物质基础及最佳配伍。本项目不仅能揭示TGP抗过敏性哮喘作用机制，同时为开发新抗过敏哮喘药物提供思路和药物靶点。

The prevalence of allergic asthma continues to rise, but current drugs provide symptomatic relief to some, but not all, patients. Recent studies have demonstrated Gab2 molecule as a scaffold protein played a very important role in allergic inflammatory signal transduction. Our previous study found that Radix Paeoniae Alba and total glucosides of paeony (TGP) can not only inhibit the degranulation of mast cells and inflammatory cytokine release, but also reduce the alveolar inflammation in mice with allergic asthma. Our preliminary study found that the mechanism of Radix Paeoniae Alba was that inhibiting mast cell activation downstream of P-Gab2, P-Akt and P-Erk protein levels and Gab2 / Shp2 complex formation. We speculate that the effect of TGP inhibit degranulation so as to achieve the role of anti-allergic asthma through the regulation of Gab2 signaling in mast cells. This project aims to use Gab2 transgenic mice to clear the pharmacological activity of TGP anti-allergic asthma through regulation of Gab2 signal anti-asthma model; using siRNA, iTRAQ quantitative proteomics and transcriptome expression profile microarray technology, to reveal the regulation of TGP on multiple targets with Gab2 as the center of asthma by spectral efficiency and network; and cooperative study and compatibility of the material basis of TGP. The expected results of this project not only can understand the anti-allergic asthma mechanism of TGP, but also for the development of new anti-allergic asthma medication to provide ideas and drug targets.