EGFR通过Glut1调控脓毒症中CD4+T淋巴细胞激活与凋亡的分子机制研究

申请者和国外同行专家都在2015年证实了EGFR抑制剂能够显著提高脓毒症小鼠的存活率，但是相关机制都是集中在EGFR对炎症因子释放的调控。而EGFR是否影响到脓毒症免疫反应，特别是对CD4+T淋巴细胞激活以及功能的调节，到目前为止相关研究都还是空白。申请者前期研究发现脓毒症中CD4+T淋巴细胞膜上的EGFR表达增加，抑制EGFR的磷酸化不仅能显著抑制CD4+T淋巴细胞激活的标记物Glut1在细胞膜上的表达，还能够缓解CD4+T淋巴细胞的凋亡，维持一定CD4+T淋巴细胞的数目，减少脓毒症诱发的多器官损伤。在此基础之上，本研究拟进一步深入探讨脓毒症中：1. CD4+T淋巴细胞膜表面EGFR激活的分子机制；2. EGFR调控Glut1细胞内转运的分子机制；3. EGFR/Glut1对CD4+T淋巴细胞激活、分化以及凋亡的影响；4. EGFR/Glut1通路对脓毒症后期免疫抑制和免疫不应答的影响。

We and other researchers have reported in 2015 that EGFR inhibitors can significantly improve the survival rate of septic mice. So far, the related mechanical studies are mainly focused on the regulation role of EGFR on the release of inflammatory mediators. Whether EGFR affects the immune response to sepsis, especially the regulation of CD4+T lymphocyte activation and function, is still remained unknown. Our previous experiments showed that expression of EGFR on the cell membrane of CD4+T lymphocyte would increase in response to LPS. Inhibition the phosphorylation of EGFR not only inhibited the cell membrane expression of Glut1, a marker of CD4+T lymphocyte activation, but also decreased CD4+T lymphocyte apoptosis, maintaining a certain number of CD4+T lymphocytes, and attenuated sepsis-induced multiple organ damage. Based on these results, this study intends to further explore in sepsis: 1. the molecular mechanism of EGFR activation on the membrane surface of CD4+T lymphocyte; 2. the molecular mechanism of EGFR regulating the intracellular transport of Glut1; 3. the effect of EGFR/Glut1 on the activation, differentiation and apoptosis of CD4+T lymphocyte; 4. the role of EGFR/Glut1 on immunosuppression and immune non-response in the late stage of sepsis and related mechanisms, and finally strive to form a theoretical system in the study of EGFR’s role on sepsis immunity.