Cbl-b/C-Cbl双敲除DC在小鼠肝硬化发生发展中的作用及机制研究

肝硬化是由多种机制诱导的肝细胞损伤，从而引起肝脏的坏死性炎症和纤维化形成所导致的一类慢性肝病。其发病率和致死率在全球呈现不断上升的趋势。近年来报道认为免疫细胞在肝硬化发生，发展过程中同样发挥很重要的作用。本研究中我们的预实验结果显示当在DC中特异性同时敲除Cbl-b/C-Cbl后，HE染色显示小鼠有严重的肝硬化症状。肝脏和脾脏DC亚群比例发生变化，且DC分泌的IFNr、IL-12、IL-6、IL10等细胞因子升高。小鼠在4-6月左右死于肝硬化。肝脏和脾脏中CD4、CD8T细胞呈现活化状态，MDSC比例升高。在此预实验基础上，我们拟通过现代细胞生物学和分子生物学手段进一步明确Cbl-b/C-Cbl对DC生物学功能的影响，通过基因敲除小鼠和嵌合小鼠模型，明确是DC细胞本身还是DC通过其它免疫细胞导致小鼠发生肝硬化；并进一步探讨Cbl-b/C-Cbl影响DC生物学功能的具体分子机制。

Cirrhosis is a chronic disease results from different mechanisms of liver injury that lead to necroinflammation and fibrogenesis. The mortality and mobility are increased in the worldwide. Recently, it was reported that immune cells play import roles in the formation of liver cirrhosis. In the present study, the mice display sever liver fibrosis and cirrhosis under HE staining when Cbl-b and C-Cbl both were ablated in dendritic cells. The subsets of DC either in spleen or in liver were changed. Also Cbl-b/C-Cbl deficient DC produce higher IL-6, IL-12, IFNr and IL-10, compared to the control DC. Finally, the dKO mice died from liver cirrhosis in 4-6 month years old. FACS analysis suggests that CD4/CD8 T cells were activated in liver and spleen. The percentage of MDSC was increased. Based on above preliminary data, we intent to further study the role of Cbl-b/C-Cbl on the DC biological function by modern cellular and molecular techniques. Through Knock out and chimera mice model to extensively point out it is DC itself or induce liver cirrhosis by other immune cells, and explore the detail mechanisms of Cbl-b/C-Cbl in DC.