Rap1/NF-κB信号通路介导间充质干细胞对气道变应性炎症免疫调控的作用研究

间充质干细胞（MSC）具有广泛的免疫调节作用，我们近期又报道了诱导性多能干细胞(iPSC)来源的MSC可抑制气道变应性炎症，但有关其内在机制的研究一直无明朗的指向。NFκB可参与介导MSC对巨噬细胞的免疫调节，近期发现Rap1是NFκB的上游关键调节因子。我们前期证实iPSCMSC受刺激后Rap1/NFκB呈激活状态，敲除Rap1基因的MSC对变应性炎症的抑制作用显著减弱，且细胞内NFκB的活化亦显著下调。这提示Rap1/NFκB可能是MSC发挥免疫调节的内在调控机制。我们拟应用敲除了Rap1基因的小鼠和iPSCMSC，采用细胞共培养和动物模型探讨Rap1/NFκB是否参与介导MSC的免疫特性；其具体分子机理；是否介导了对小鼠气道变应性炎症的免疫调节。iPSCMSC具有强大的应用优势，本研究将从其内部变化而非其作用靶细胞的角度阐明具有免疫调控作用的分子机制，为真正走向临床提供切实的理论依据

The unique immunomodulatory properties of mesenchymal stem cells (MSCs) have been determined. Recently, we reported that induced pluripotent stem cell(iPSC)-drived MSCs had immunosuppressive effect on allergic airway inflammation in mouse (Stem Cells, 2012). However, the possible mechanims about the change of MSCs to promote immunomodulation is unclear. Fortunately, bone-marrow MSCs was reported to regulate macrophages via its intracelluar NF-κB pathways. Rap1, a telomeric interacting protein was recently reported to be an upstrem and critical regulator of NF-κB. We next found that both Rap1 and NFκB wer activated in iPSCMSC under the stimulation of tumor necrosis factor-α. In addtion, bone marrow dervice MSCs from Rap1 knockout mice had weaker inhibition to allergic airway inflammation in mice and had no activation of NF-κB pathways under the stimulation. Therefore, we hypothesize that Rap1/NF-κB signal pathway plays a key role in the immunomodulatory effect of (iPSC-)MSCs. In this project, we will use the Rap1 knockout mice and iPSCMSCs with Rap1 gene knowckout to investigate (1) the role of Rap1/NF-κB signal pathway in the immunomodulatory effect of (iPSC-)MSCs and the possible downstream pathways; (2) especially the role of Rap1/NF-κB signal pathway in the immunosupression of (iPSC-)MSCs on allergic airway inflammation. iPSCMSCs have more advantages compared to adult MSCs. This study is timely and may provide useful information to the mechanism ofimmunomodulation of (iPSC-)MSC on allergic airway inflammation.