miR-449a调控Notch信号通路在移植物排斥中的作用和机制

Modulation of Th1/Th2 balance and its related cytokine spectrum is very important to prevent allograft rejection during transplantation. Notch signaling pathway plays regulatory roles in CD4+ T cell differentiation, DLL1 ligand on APC and Notch1 receptor on CD4+ T cell mediate Th1 or Th2 polarization, respectively. Our pilot study showed that miR-449a expression was increased in graft infiltrating lymphocytes during allograft rejection, which associates with CD4+ T cell functions. Since miR-449a inhibits its targets, DLL1 and Notch1, suggesting that miR-449a may regulate Th1/Th2 balance via Notch signaling pathway and contribute to alloimmune responses. In this study, we will utilize a therapeutic inhibition approach targeting on miR-449a to investigate the roles of miR-449a in Th1 and Th2 responses as well as in cytokines composition posttransplant. We will study whether miR-449a inhibition is beneficial to allograft survival. We will also evaluate the association of miR-449a expression with immune status of recipient. Our results will clarify the specific role of microRNA in immune responses during transplantation and provide important significance in basic research and clinical application.

器官移植术后调控受者Th1/Th2细胞平衡和Th1、Th2型细胞因子水平对控制移植物排斥具有重要意义。Notch信号通路对CD4+T细胞分化具有调节作用，APC上的DLL1配体和CD4+T细胞上的Notch1受体分别介导Th1和Th2极化。我们发现移植物排斥致miR-449a在浸润淋巴细胞中表达升高，其表达与CD4+T细胞功能相关。因miR-449a抑制其靶基因DLL1和Notch1表达，提示其可能通过notch信号通路调控Th1/Th2细胞平衡，参与同种异体免疫反应。本课题拟靶向干预miR-449a的表达，研究其在器官移植术后对Th1和Th2应答以及相关细胞因子组成的影响，探索抑制miR-449a的表达是否有益于移植物存活，并评估血清中miR-449a的表达是否与受者的免疫状态相关。本课题若获成功，将阐释特异的microRNA在器官移植中的免疫学机制，对基础研究和临床应用具有重要的意义。