泛素化连接酶FBXL19通过调节血管内皮细胞炎症调控急性肺损伤的作用和分子机制研究

急性肺损伤(ALI)最严重阶段为急性呼吸窘迫综合征（ARDS），以肺泡-毛细血管屏障损伤导致的肺水肿为核心病理特征，具有很高的发病率和死亡率。血管内皮细胞炎症是导致肺泡-毛细血管屏障损伤的基础。我们前期研究发现泛素化连接酶（E3）FBXL19在TNF-α诱导的血管内皮细胞炎症中显著下调，推测其可能在此过程中发挥重要作用。本课题我们拟首先研究FBXL19肺炎患者和脓毒症诱导的ALI小鼠肺血管内皮系统以及体外血管内皮细胞炎症模型中的表达变化；进一步在动物和细胞水平明确FBXL19通过调节血管内皮系统炎症调控ALI的作用；最终在分子水平探明FBXL19作为E3调控的靶向蛋白和分子调节机制。本研究不但将深化对FBXL19功能的认知，也为ALI及与血管内皮细胞炎症有关疾病的治疗提供了新靶点。

Acute lung injury (ALI) is a clinical syndrome characterized by pulmonary edema caused by the alveolar-capillary barrier damage. Acute respiratory distress syndrome (ARDS) is the most severe stage of ALI, which can cause high morbidity and mortality. Vascular endothelial cell inflammation is the key factor for alveolar-capillary damage. Previous studies found that ubiquitin ligase (E3) FBXL19 was obvious decreased in the cell model of TNF-α-induced vascular endothelial cell inflammation. It suggests that FBXL19 may play an important role in this process. This project will be performed from four progressive levels of "human-animal-cell- molecule". The expression of FBXL19 in pulmonary vascular endothelial system of pneumonia patients and sepsis-induced ALI mice, as well as vascular endothelial cell inflammation model will be determined. Conditional FBXL19 gene knock in mice and sepsis-induced ALI models will be used to investigate the effects of overexpression of FBXL19 in vascular endothelial system on ALI induced mortality, inflammation and vascular endothelial permeability. The gene overexpression and siRNA interference will be used to determine the role of FBXL19 in vascular endothelial inflammation. The targeted proteins and molecular mechanisms of FBXL19 as E3 also will be identified. This project will provide a new target for the treatment of ALI and some diseases with vascular endothelial cell inflammation