急性肺损伤是重症监护病房临床常见但病情复杂的一种综合症，其发病机制目前尚不清楚。由于没有有效的药物治疗，其死亡率仍然很高。通过前期研究我们发现E3泛素连接酶TRIM65的基因敲除小鼠在急性肺损伤中死亡率显著上升，并从内皮细胞和巨噬细胞中分别成功筛选到其相互作用蛋白VCAM-1和C/EBPδ。我们推测，TRIM65通过泛素化降解内皮细胞中的VCAM-1，降低内皮细胞对单核细胞特别是巨噬细胞的粘附；同时通过泛素化降解巨噬细胞中的C/EBPδ，抑制炎症因子的转录，从而抑制炎症反应。本项目将从细胞系、原代细胞、小鼠模型系统全面揭示TRIM65在急性肺损伤中的作用，并利用TRIM65全身敲除鼠和巨噬细胞条件性敲除鼠以及TRIM65与内皮细胞条件性敲除VCAM-1的双敲小鼠深入阐明具体的分子机制，并探索有效的治疗药物，将基础研究与转化医学有机结合，为急性肺损伤的诊疗提供新的理论依据和思路。

Acute lung injury (ALI) is a common clinical syndrome in ICU departments with complex condition. The pathology of ALI is still not clear and there is no specific and efficient treatment against ALI. Since there is no effective pharmacological treatment for ALI, its mortality rate remains high. Based on our preliminary studies, we found that E3 ubiquitin ligase TRIM65 knockout mice significantly increased mortality in acute lung injury and then we successfully screened its interaction proteins in endothelial cells (VCAM-1) and macrophages(C/EBPδ) by GST pull-down assay. We hypothesized that TRIM65 degrades VCAM-1 in endothelial cells by ubiquitination, and reduces the adhesion of monocytes especially macrophages to endothelial cells. At the same time, it ubiquitinates and degrades C/EBPδ in macrophages, then inhibits the transcription of inflammatory factors and inflammatory response. This project will reveal the role of TRIM65 in acute lung injury from cell lines, mice primary cells, and mouse model systems, and use TRIM65 systemic knockout mice and macrophage conditional knockout mice as well as double knockout mice of TRIM65 and VCAM-1 which is endothelial cell conditional knocked out to clarify the specific molecular mechanisms, meanwhile explore effective therapeutic drugs, and combine basic research with translational medicine to provide a new theoretical basis and direction for the diagnosis and treatment of acute lung injury.