波状蛋白（VIM）介导脓毒症时免疫细胞凋亡的作用和机制研究

Sepsis is the most common cause of death in the clinical critically ill patients. We have successfully screened the sepsis biomarkers by clinical proteomics approach and found that Vimentin (VIM) played an important role in the occurrence and development of sepsis. However, the exact mechanism is remaining unclear. In this study, the relationship between the changes of peripheral circulation VIM expression and different stages of sepsis development will be further verified in lager clinical trials, as well as the relationship between VIM expression and apoptosis of immune cells (e.g lymphocytes) will also be clarified. More importantly, with the VIM of immune cells overexpressed and inhibited, we will explore the influence of VIM on immune cells in the process of apoptosis and proinflammatory/inflammatory suppression status and its relevant mechanism through the cell model in vitro. This may indicate that the role of VIM in the cell-mediated immunity apoptosis and inflammation-related pathways. Through the implementation of this study, we can clarify the clinical value of VIM and the mechanism of VIM-mediated immune cell apoptosis during the sepsis development from the molecular level, and determine whether the VIM as a new target for sepsis diagnosis and treatment.

脓毒症是临床危重病患者最常见的死因。我们前期通过脓毒症临床蛋白质组学研究筛选并发现了波状蛋白（Vimentin，VIM）在脓毒症的发生和发展中具有重要作用，但具体机制尚不清楚。本研究拟通过临床实验进一步验证循环中VIM的表达与脓毒症发生发展的不同阶段的关系，以及阐明VIM在免疫细胞（例如淋巴细胞）上的表达与凋亡的关系。另外，利用体外细胞模型，借助过表达和抑制免疫细胞的VIM，深入探究VIM对免疫细胞凋亡与促炎抑炎状态的影响机制，说明VIM在介导免疫细胞凋亡和炎症相关通路中的作用和地位。通过本课题的实施，旨在探索VIM的临床应用价值，从分子水平阐明VIM介导脓毒症时免疫细胞凋亡的相关发生机制，最终确定VIM作为脓毒症诊断和治疗的生物靶标的可行性。

研究者近年来致力于脓毒症的标志物和靶点研究。前期通过蛋白质组学技术发现波状蛋白可能会是一个潜在脓毒症的靶点和分子标记。有研究证实波状蛋白在中性粒细胞和巨噬细胞的炎症调控有重要作用。尤其是Nat Commun 2016年上的一篇关于VIM调控ARDS炎症反应所致的肺组织损伤与修复，极大地印证了VIM的潜在价值。并且2017年Cells上提到了感染性疾病中波状蛋白的表达显著的客观现象。但是具体机制尚不明确。本研究首先利用临床患者样本，进一步证明波状蛋白对于脓毒症的患者的诊断以及不同脓毒症严重程度和预后的患者的鉴别进行了临床实验验证。其次利用体外细胞模型，借助过表达和抑制单核细胞和淋巴细胞的波状蛋白，深入探究波状蛋白对单核和淋巴细胞凋亡与促炎抑炎状态的影响机制。得出波形蛋白可通过调节促炎和抗炎细胞因子的平衡，通过调节脓毒症中的单核细胞活力和凋亡状态来调节先天免疫的结论。最后将该发现继续延伸到ARDS研究中，发现VIM早期可以通过激活肺成纤维细胞线粒体自噬途径降低LPS所致线粒体氧化应激和炎症反应防止肺损伤的进一步发生，补充了ARDS的机制。综合上述研究结果，可以初步证实波状蛋白有可能成为脓毒症诊断和干预的新靶点，在未来的研究中具有相当的潜力和价值。