Rap1/NF-κB信号通路介导间充质干细胞的免疫调理作用及其强化表达对PR-MODS的防治

间充质干细胞（MSC）具有免疫调节作用，我们发现诱导性多能干细胞(iPSC)来源的MSC可调控心跳骤停后多脏器功能不全综合征（PR-MODS）的免疫紊乱并提高生存率、且疗效更强。但决定MSC具有免疫调节作用的内部机制尚不明确。我们对PR-MODS模型动物的MSC进行了基因分析，发现端粒相关抑制和激活蛋白1(Rap1)的表达量显著升高，文献报道其参与免疫调节。而核因子NF-κB与MSC的免疫调节有关，我们的预实验提示其可受Rap1调节。可以假说，干细胞发挥免疫调理的内部机制可能是由Rap1/NF-κB介导的。本课题拟采用多种敲除或沉默了Rap1及IKKβ基因的MSC，利用细胞共培养和动物模型探讨Rap1/NF-κB是否是决定MSC免疫调节作用的分子机制及其上下游关系；刺激增强Rap1表达是否可以进一步强化其作用。本研究将有助于理解干细胞发挥作用的机制，也必将提供更好的干细胞治疗方法。

Mesenchymal stem cells (MSCs) exert immunomodulation. We found that MSCs derived from induced pluripotent stem (iPS) cells reduce the inflammation and organ dysfunction of post-resuscitation multiple organ dysfunction syndrome (PR-MODS) and significantly increased survival rate and had better effects compared to MSCs derived from the adult tissues . However, the possible mechanims about the change of MSCs to promote immunomodulation is unclear. We collected the MSCs from PR-MODS animals and did genemicroarray. We found that the levels of gene Rap1 significantly increased. Rap1 was recently reported to have the ability of immune modulation. NF-Κb is an important signaling pathway on the immunemodulation of MSCs. 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 iPSC-MSCs with Rap1 and NF-κB gene knockout to investigate (1) the role of Rap1/NF-κB signal pathway in the immunomodulatory effect of (iPSC)-MSCs in PR-MODS and the relationship between Rap1 and NF-κB; (2) the furthur effects of increasing Rap1 function in iPSC-MSCs. This study is timely and will provide useful information to the mechanism of immunomodulation about iPSC-MSC on PR-MODS especially in clinical trails.