去泛素化酶USP10介导Notch3通路在宫外生长受限引起肺动脉高压的机制研究

生命早期是影响整个生命健康的关键发育时期。出生后营养严重缺乏引起的宫外生长受限 (EUGR) 会导致各种心血管发育疾病，特别是肺动脉高压(PAH)。申请人前期研究发现出生后营养限制诱导的EUGR大鼠12周时平均肺动脉压升高，伴Notch3信号通路激活，且肺血管平滑肌细胞增殖迁移增加；体外抑制泛素特异性蛋白水解酶ubiquitin-specific peptidase 10 (USP10) 减少肺血管平滑肌细胞的增殖迁移。我们推测去泛素化酶USP10参与Notch3受体的泛素化转换，从而影响平滑肌细胞增殖和迁移。本项目拟进一步考察去泛素化酶USP10与Notch3胞内蛋白（Notch3ICD）在肺动脉平滑肌上的表达特点，探索两者相互作用，阐明USP10介导Notch3通路泛素化的机制。项目的实施可望为EUGR肺动脉高压诊治潜在靶点提供新颖的科学依据。

Early life is a critical developmental period that affects the health of the whole life. Extrauterine growth restriction (EUGR) caused by severe nutritional deficiencies after birth can lead to a variety of cardiovascular developmental diseases, especially pulmonary arterial hypertension (PAH). In pulmonary hypertension, pulmonary artery smooth muscle cells have the characteristics of increased proliferation and migration, but the mechanism is unknown. The applicant's previous study found that the mean pulmonary artery pressure of EUGR rats induced by postnatal nutritional restriction increased at 12 weeks, accompanied by activation of Notch3 signaling pathway, and the proliferation and migration of pulmonary artery smooth muscle cells increased. In vitro, inhibition of ubiquitin-specific peptidase 10 (USP10) reduces migration of pulmonary vascular smooth muscle cells. We speculate that the deubiquitination enzyme USP10 is involved in the ubiquitination conversion of Notch3 receptor, thus affecting the proliferation and migration of smooth muscle cells, which needs to be further studied. This project intends to further investigate differences of the expression of the Notch3 intracellular protein (Notch3ICD) in pulmonary artery smooth muscle and explore the interaction between USP10 and Notch3ICD. It was demonstrated that the increase or deletion of USP10 had an impact on the protein degradation of Notch3ICD and the ability of cell proliferation and migration, and the mechanism of USP10-mediated ubiquitination of Notch3 pathway was elucidated. The implementation of the project is expected to provide a novel scientific basis for the diagnosis and therapeutic targets of EUGR pulmonary hypertension.