CCN3调控TGF-β/Smad信号通路抑制EndoMT在胸主动脉瘤/夹层发生发展中的机制研究

胸主动脉瘤/夹层严重威胁生命健康，病情凶险，致死率高，其发病机制尚未完全阐明。新的研究发现内皮间质样转换（EndoMT）在胸主动脉瘤/夹层的发生发展中充当重要角色。前期实验表明内皮细胞CCN3缺失可以促发胸主动脉瘤/夹层。结合国内外研究，提出假设：CCN3调控TGF-β/Smad信号通路抑制EndoMT改善胸主动脉瘤/夹层的发生发展。本课题拟通过人体胸主动脉瘤/夹层的组织标本和内皮细胞培养，检测EndoMT标志物的表达；继而采用组织特异性CCN3敲除结合AngII灌注建立小鼠胸主动脉瘤/夹层模型，明确CCN3缺失导致EndoMT促使胸主动脉瘤/夹层的发生；过表达或沉默主动脉内皮细胞CCN3，进一步阐明CCN3蛋白调控TGF-β/Smad途径抑制EndoMT的机制。相关研究可为胸主动脉瘤/夹层的发病机制提供新的理论基础和干预靶点。

Thoracic aortic aneurysm/dissection is a critical and emergency disease with high mortality. The pathogenesis has not been fully elucidated. The new study found that endothelial–mesenchymal transition (EndoMT) plays an important role in the development of thoracic aortic aneurysm/dissection. Previous studies have shown that loss of CCN3 in endothelial cell can promote thoracic aortic aneurysm/dissection.Combined with domestic and foreign studies, we speculated that CCN3 regulation of TGF-β/Smad signaling pathway inhibition of EndoMT plays an important role in the occurrence and development of thoracic aortic aneurysm/dissection.This study intends to detect the expression of EndoMT markers by tissue specimens and endothelial cell cultures of thoracic aortic aneurysm/dissection.Then, the tissue-specific CCN3 knockout combined with AngII perfusion was used to establish the thoracic aortic aneurysm/dissection model in mice, which illustrating that EndoMT caused by CCN3 deletion promotes the occurrence of thoracic aortic aneurysm/dissection. Overexpression or silencing of CCN3 in aortic endothelial cells further elucidates the mechanism that CCN3 protein regulates TGF-β/Smad pathway to inhibit EndoMT. Related research can provide a new theoretical basis and intervention target for the pathogenesis of thoracic aortic aneurysm/dissection.