LPS促进MDSCs扩增和极化的分子机制研究

MDSC是一群新的免疫抑制性细胞，在肿瘤、感染、创伤等疾病中发挥重要作用。我们前期的研究发现LPS不仅能使MDSC扩增，且能使其向M1型细胞极化,进而减弱MDSC的抑制功能和Treg转化功能。但其分子机制还不清楚。很多研究表明microRNA参与了众多的生物学过程，为探讨LPS是否通过microRNA来调控MDSCs的扩增和极化，我们首先通过基因芯片检测LPS处理的MDSCs的microRNA表达谱，实验结果显示，LPS可以提高MDSC的let-7e等microRNA表达。进一步通过建立let-7e嵌合小鼠模型，应用FACS分析发现：过表达let-7e能使MDSC比例升高。因此，本研究拟在已有研究基础上，建立let-7e转基因模型，进一步探讨LPS对let-7e表达的转录调控分子机制，并寻找let-7e靶基因，探讨LPS 通过let-7e调控MDSCs的扩增和极化的分子机制。

MDSC is a newly defined population of immunosuppressive cells. These cells play very important roles in many diseases such as tumor, infection and trauma, etc. Ours and other studies showed that LPS can induce the expansion of MDSCs, but the detail mechanism remains unclear. Our current study demonstrates that LPS can not only induce the expansion of MDSCs, but also drive the MDSCs to polarize to M1 type cells. Meanwhile,the suppressive function and the ability of converting the CD4+CD25- T cells into CD4+CD25+Foxp3+ T cells were decreased in LPS-treated MDSCs . Microarray and real time PCR results suggested that the expression of Let-7e was up-regulated in LPS-treated MDSCs. Let-7e chimera mice model displayed that once Let-7e overexpressed, the percentage of MDSCs will be increased. Therefore, in this proposal, we intent to extensively explore the underlying mechanism of regulation of LPS on the transcription of Let-7e, and establish Let-7e transgenic mouse model to further study the fucntion and molecular mechanism of Let-7e on MDSCs.