经AMPK/DBC1-SIRT1途径调节Treg细胞功能在肺移植急性排异中的作用及机制

通过调节性T细胞(Treg)诱导，建立受体移植耐受是解决肺移植急性排异的重要策略之一。如何上调受体Treg细胞功能改善肺移植急性排异值得进一步研究。最新研究发现，沉默信息调节因子1 (SIRT1)去乙酰化酶活性表达与Treg细胞免疫调节功能负相关；乳腺癌缺失基因1(DBC1)蛋白与SIRT1动态结合形成复合体抑制SIRT1去乙酰化酶活性；腺苷酸活化蛋白激酶(AMPK)激活可能对DBC1-SIRT1复合体产生影响。申请者前期发现，抑制SIRT1活性可上调体外炎性环境或移植受体中Treg细胞功能。由此推测：抑制DBC1-SIRT1复合体解离，依赖DBC1对SIRT1的内源性抑制，具备上调Treg细胞免疫调节功能的可能。本课题拟通过体内、体外实验，研究肺移植后经AMPK途径调控DBC1-SIRT1复合体结合状态，上调Treg细胞功能并改善肺移植急性排异反应的作用及机制。

Establishing recipient transplantation tolerance is one of the most crucial strategies to solve acute lung allograft rejection through regulatory T cells induction. It is yet to be discovered how to up-regulate recipient Treg cells function in order to attenuate acute lung allograft rejection. Recent studies revealed that deacetylase activity expression of silent information regulator 1 (SIRT1) has negative correlation with Treg cells immune-regulatory function. Besides, deleted in breast cancer 1 (DBC1) protein bound with SIRT1 dynamically. Then, DBC1 inhibited SIRT1 function. Adenosine monophosphate- activated protein kinase (AMPK) activation may have an effect on the DBC1-SIRT1 complex. Our previous studies found out that inhibiting SIRT1 activity can up-regulate Treg cells function in vitro pro-inflammatory milieu or in transplant recipients. We inferred that repressing DBC1-SIRT1 complex dissociation and maintaining endogenous DBC1-dependent inhibition to SIRT1 could up-regulate immune-regulatory function of Treg cells. Based on in vivo and in vitro experiments, our study will focus on the regulation of DBC1-SIRT1 complex, up-regulating Treg cells function and attenuating acute lung allograft rejection through AMPK after lung transplantation.