结核感染中miR-155通过SOCS家族上调γ-干扰素介导巨噬细胞凋亡机制的研究

巨噬细胞凋亡是人体清除结核杆菌的重要途径。γ-干扰素介导的JAK-STAT通路在巨噬细胞凋亡中发挥关键作用，而细胞因子信号转导抑制分子（SOCS）家族可特异性抑制JAK激酶活性。我们前期研究发现，结核感染后巨噬细胞内SOCS1与miR-155表达依次升高，且生物信息学预测SOCS1和SOCS6 存在miR-155结合位点。故我们推测miR-155可能通过下调SOCS家族放大γ-干扰素介导的巨噬细胞凋亡过程。本课题拟研究：①结核感染不同阶段miR-155、SOCS1、SOCS6表达的动态变化及时间特异性；②miR-155调控SOCS1及SOCS6的作用靶点；③miR-155是否通过SOCS1、SOCS6及JAK-STAT通路上调γ-干扰素介导巨噬细胞凋亡及其具体机制。本研究将从细胞和动物水平了解miR-155在结核感染后巨噬细胞凋亡中的机制。可为寻找新的结核病防治干预靶点提供理论依据。

Macrophage apoptosis is an important way to clear mycobacterium tuberculosis (MTB) in human. JAK-STAT pathway mediated by IFN-γ plays a key role in macrophage apoptosis,and the suppressor of cytokine signaling (SOCS) family could specifically inhibit the activity of JAK kinase.Our previous research has proved that the SOCS1 and microRNA-155 (miR-155) increased successively in macrophage infected by MTB. Meanwhile,the bioinformatics predicted that the SOCS1 and SOCS6 gene existed miR-155 binding sites. Therefore, we hypothesized that miR-155 may enlarge the IFN-γ-mediated macrophage apoptosis process by down-regulating SOCS family. In this proposal, we intend to analyze the dynamic changes and time-specificity of miR-155, SOCS1, and SOCS6 in different stages of macrophage which is infected by MTB. At the same time, the target sites of miR-155 which can regulate SOCS1 and SOCS6 in macrophage will be investigated. Further, we will explore the mechanism if miR-155 up-regulates IFN-γ-mediated macrophage apoptosis process by SOCS1, SOCS6, and JAK-STAT pathways. In this sthdy, we understand the mechanism of miR-155 in macrophage apoptosis after infected by MTB at cell and animal level. The results will provide a theoretical basis to find new targets for tuberculosis prevention and treatment.