高迁移率族蛋白B1(HMGB1)参与了失控性炎症反应及免疫障碍的病理过程。调节性T细胞(Treg)具有负向调节免疫效应。申请人在前期的研究中已证明PTEN在HMGB1诱导的ALI中的关健作用。本课题将以调控机制中的“开关”β--catenin基因为关键突破口，以HMGB1、PTEN、TGF-β等通路相关基因以及Tregs为主要研究对象，利用基因敲除模式小鼠，在体内和体外分别解析β-catenin介导HMGB1/PTEN信号胞内促生存通路和对胞外的Tregs诱导，从天然免疫调控特异性免疫这一新的角度解释β--catenin的作用，有利于深化对脓毒症肺损伤后免疫功能紊乱信号转导机制的认识，为靶点药物和细胞治疗提供新思路。

High Mobility Group Box-1 Protein (HMGB1) as a new late cytokines mediator participate in pathologica process, such as inflammatory reaction out of control and immune dysfunction. Regulatory T cell (Treg) has the negative regulation of immune responses. It is very important for keeping in immune balance of body. In the previous study, we have found PTEN plays an important role in ALI induced by HMGB1 and PTEN deficiency can lead to the accumulation of β-catenin in the cell nucleus, which suggests that the β-catenin may play a role in the downstream signal pathway of PTEN. Based on the previous research achievements on PTEN, this project will take the "switch" β-catenin gene of the regulation mechanism as the key breakthrough, and pathway related genes, i.e. HMGB1, PTEN, PDK1, Akt, TGF-β, and Foxp3+ Tregs as the main research object. Through the construction of conditional knockout β-catenin M-KO (Myeloid specific lack of β--catenin) mice, analysis on β--catenin gene mediating signal HMGB1/PTEN intracellular Pro survival pathway and its effect on extracellular Tregs will be perfomed in the in vivo and in vitro. The analysis will focus on the interplay between signal pathway gene and the β-catenin. The signal mechanism of the precise modulation of natural immune HMGB1/PTEN/β-catenin on Treg will be studied to explain the role of β-catenin from a new perspective of the natural immune regulation of specific immunity. This will deepen the understanding of the signal transduction mechanism of immune dysfunction after acute lung injury and provide a new target for drug or cell therapy.