USP14在低氧诱导肺血管内皮细胞重构中的作用和机制

Hypoxia induced pulmonary artery endothelial cells damage induced by oxidative stress, inflammation, apoptosis; in the trend of the effect factor and inflammatory factor, raise bone marrow-derived endothelial progenitor cell migration and differentiation, eventually leading to endothelial cell proliferation and phenotypic transformation. Is an important initial step of remodeling of the pulmonary arteries induced by hypoxia and progressive factor. The ubiquitin proteasome system plays an important role in the vascular remodeling of pulmonary artery induced by hypoxia. USP14 is related to the proteasome, and its specific small molecule inhibitor IU1 can enhance the function of the proteasome. USP14 can regulate IRE1, NF- nuclear factor kappa CXCR4, B and other kinds of hypoxic pulmonary vascular remodeling related protein. The research content of this thesis: through hypoxia intervention co culture of bone marrow-derived endothelial progenitor cells and endothelial cells immunofluorescence, ELISA, RT-PCR, Western blot method to clarify the endothelial cells play an important role in hypoxic pulmonary vascular remodeling of USP14 through the mechanism of the regulation of IRE1, NF kappa B and CXCR4 in the regulation of endothelial cell function. Finally, using the IU1 intervention model of rats with hypoxic pulmonary hypertension, and further clarify the important role of USP14. To provide a new therapeutic target for the treatment of hypoxic pulmonary hypertension.

低氧诱导肺小动脉内皮细胞氧化应激损伤、炎症、凋亡；在趋化因子、炎症因子的作用下，募集骨髓源性内皮祖细胞迁移分化，最终导致内皮细胞增殖和表形转化。是低氧诱导的肺小动脉血管重构的重要起始环节和促发因素。泛素蛋白酶系统在低氧诱导的肺小动脉血管重构发挥着重要作用。USP14是蛋白酶体相关的去泛素化酶，其特异性小分子抑制剂IU1能增强蛋白酶体功能；USP14能调控IRE1、NF-ΚB、CXCR4等多种低氧肺血管重构相关蛋白。本课题的研究内容：通过低氧干预共培养的骨髓源性内皮祖细胞与内皮细胞细胞的方法，阐明内皮细胞在低氧肺小动脉血管重构的变化机制和重要作用，以及USP14在肺血管重构的不同阶段调控内皮细胞功能的作用机制。最后利用IU1干预低氧肺动脉高压模型大鼠，进一步阐明USP14的重要作用。为低氧肺动脉高压的基础和临床提供一个新的治疗靶点。

低氧诱导肺小动脉内皮细胞氧化应激损伤、炎症、凋亡。在趋化因子、炎症因子的作用下，募集骨髓源性内皮祖细胞迁移分化，最终导致内皮细胞的增殖和表形转化。这是低氧诱导的肺小动脉血管重构的重要起始环节和促发因素。泛素蛋白酶系统在低氧诱导的肺小动脉血管重构发挥着重要作用。USP14是蛋白酶体相关的去泛素化酶，其特异性小分子抑制剂IU1能增强蛋白酶体功能。USP14可调控IRE1、NF-ΚB、CXCR4等多种低氧肺血管重构相关蛋白。本项目旨在阐明去泛素化酶USP14调控低氧诱导内皮细胞凋亡骨髓内皮祖细胞分化和内皮细胞的增值及表形转化的分子机制。证实去泛素化酶USP14在低氧诱导肺小动脉血管重构、肺动脉高压、右心肥大的作用，并探讨其机制。实验显示USP14在低氧诱导内皮细胞重构时明显上升，以及应用特异性抑制剂后的明显改善。接下来希望能建立大鼠骨髓内皮祖细胞和肺小动脉内皮细胞共培养系统，通过低氧干预共培养的骨髓源性内皮祖细胞与内皮细胞，阐明内皮细胞在低氧肺小动脉血管重构的重要作用，探讨USP14通过调控IRE1、NF-κB、CXCR4调控内皮细胞功能的作用机制。为低氧肺动脉高压的研究和药物开发提供一个新的靶点。