P2Y12调控VICs衰老促进主动脉瓣钙化机制研究

钙化性主动脉瓣膜病（CAVD）高发且严重危害健康，其发病率随年龄增加而显著上升，但目前缺乏有效的药物防治措施。研究表明瓣膜间质细胞（VICs）是瓣膜钙化的主要效应细胞，细胞衰老在诸多疾病中发挥关键作用，但在CAVD作用及调控机制目前并不明确，我们前期研究发现CAVD瓣膜中存在VICs衰老，而P2Y12激活是VICs衰老的重要诱因，药物抑制P2Y12可减轻VICs衰老及新西兰兔的瓣膜钙化，我们推测P2Y12可调控VICs衰老进而促进主动脉瓣钙化。因此设计本项目，拟首先分析钙化瓣膜中VICs衰老、P2Y12和钙化的相关性，然后构建瓣膜钙化动物模型，利用药物以及基因敲除技术，结合人VICs细胞实验进行验证，并进一步探讨其分子生物学调控机制，为主动脉瓣钙化发病机制和干预靶点研究提供新的依据。

Calcific aortic valve disease (CAVD) is highly prevalent and devastating, its incidence increases significantly with age. However, effective drugs for its prevention and treatment are lacking. Studies have shown that valve interstitial cells (VICs) are the main cells of valve calcification. Cellular senescence plays a key role in various diseases, but its role and regulatory mechanism in CAVD have not been elucidated. Our previous study found that the senescence of VICs existed in valves with CAVD, and P2Y12 activation was an important cause of VIC senescence. Additionally, antagonists of P2Y12 could reduce VIC senescence and valve calcification in New Zealand rabbits. Consequently, we speculate that P2Y12 can regulate the senescence of VICs and thereby promoting aortic valve calcification. Therefore, in this project, it is intended to firstly analyze the correlations of VIC senescence, P2Y12 and calcification in calcified aortic valves. Moreover, animal model of valve calcification will be established, and verification will be carried out using drugs and gene knockout combined with human VICs experiments. Further, its underlying molecular biological regulatory mechanism will be explored, so as to provide a new basis for the research on the pathogenesis and pharmacological intervention targets of aortic valve calcification.