高迁移率族蛋白B1(HMGB1)作为重要免疫调节分子参与机体免疫反应过程。线粒体-内质网结构偶联(MAM)是线粒体和内质网(ER)发生交互作用的平台，与内质网应ERS和细胞凋亡密切相关。我们前期研究发现MAM重要物理联结蛋白-线粒体融合蛋白2(Mfn2)在HMGB1调控T细胞免疫活化过程中具有重要作用，本项目拟在细胞和整体水平上进一步探讨MAM结构功能异常及其与ER间信息交流对HMGB1介导CD4+ T细胞免疫反应的影响。通过基因调控技术改变Mfn2表达水平，观察细胞和烧伤动物模型中MAM功能结构异常对HMGB1调控CD4+T细胞免疫效应的影响；应用ERS诱导剂以及对PERK/eIF-2α通路相关分子进行干预，论证MAM在HMGB1对T淋巴细胞免疫调控过程中的关键环节与意义。该研究从新的角度深化对HMGB1介导T细胞免疫功能紊乱的认识，从而为烧伤脓毒症的免疫调节治疗提供理论基础和靶点。

High mobility group protein B1 (HMGB1) could act as an important immune modulator by regulating immune cells function. Mitochondria-associated ER membrane (MAM) is the interacting platform of mitochondria and endoplasmic reticulum (ER). It is closely related to endoplasmic reticulum stress (ERS) and cell apoptosis. Our previous study found that one of MAM important physical connection proteins - mitofusin 2 (Mfn2) - plays an important role in the active process of T cell immune induced by HMGB1. This project intends to explore the significance of physical or functional abnormality of MAM as well as signal transduction between ER and MAM in immunomodulation of HMGB1 on CD4+T. CD4+T cell will be stimulated with certain concentration of recombinant HMGB-1. And with the genetic regulation of Mfn2 expression in CD4+T, as well as treatment with chemicals to induce or inhibit ERS response, the significant roles of MAM in the molecular regulation mechanism of HMGB-1 on T cells immune function, and the internal connection of MAM with the ERS pathway of PERK/eIF-2 alpha /ATF4/ will be analyzed. Based on this project, we hope to explore the impact and mechanism of MAM on T cell activation induced by HMGB1. Our findings will help to clarify the understanding of HMGB1 as an immune regulator, thus shed a light to the development of novel therapeutic strategies and targets for the immune regulation for improving the clinical outcome of patients with severe injury and subsequent sepsis.