心脏瓣膜钙化严重危害人类健康，其发病机制目前尚不明确。本课题组前期实验及诸多研究表明：慢性炎症反应在瓣膜钙化启动和进展中起重要作用；单核巨噬细胞在不同微环境刺激下极化为不同功能表型，调控局部炎症反应；JAK-STAT信号转导是炎症因子发挥效应的共同通路，广泛参与细胞增殖、分化、凋亡及免疫调节等病理生理过程；SOCS是JAK-STAT信号通路的靶基因，通过负性调控减少炎症因子及凋亡基因等表达。鉴于此，我们推测：JAK-STAT信号通路可能参与心脏瓣膜钙化的病理过程，SOCS通过抑制JAK-STAT基因表达，影响炎症反应，干预瓣膜钙化的发生发展。本项目拟通过检测人体钙化瓣膜，构建瓣膜钙化动物和细胞模型，利用shRNA体内基因沉默技术，可控性施加干预措施，探讨SOCS调控JAK-STAT信号转导通路在瓣膜炎症反应及瓣膜钙化中的作用及分子机制，为药物防治天然或生物瓣膜钙化提供新思路。

Heart valve calcification is a common clinical problem with high morbidity and mortality, and to date there are no effective drug therapy or preventive methods for it. In the past decade, an abundance of evidence have suggested that, valve calcification is not simply a passive degenerative disease, but an active pathological progress akin to atherosclerosis, including endothelial dysfunction ,lipoprotein deposition, chronic inflammation, extracellular matrix remodeling. The crucial role of chronic inflammation in valve calcification has been widely documented. Nevertheless, mechanism for chronic inflammation on valve biology is far from being fully understood..Macrophage and inflammatory cytokines constitute the main part of chronic inflammation. Depending on the microenvironment, macrophages can polarize to distinct functional phenotypes: pro-inflammatory classically activated macrophages (M1 macrophages) and anti-inflammatory alternatively activated macrophages (M2 macrophages). Recent studies demonstrate that the ratio of M1/M2 macrophages was positively correlated with the severity of coronary atherosclerosis, whereas the association between macrophage polarization and valve calcification has not been defined. Most cytokines use the so-called janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway, and this pathway also acts as a key regulator in macrophage polarization. Therefore, JAK-STAT controls the important inflammatory process. Altogether, these indicate that JAK-STAT signaling pathway may participate the pathogenesis of valve calcification..Suppressors of cytokine signaling (SOCS) proteins are target genes of JAK-STAT pathway, and they play pivotal role in negative regulation of JAK-STAT. Accumulating evidence shows that dysregulation of cytokine signaling by differential SOCS expression, especially SCOS1 and SOCS3, is involved in various inflammatory, immune and infectious diseases. SOCS were found highly expressed both in human atherosclerotic plaques and in experimental atherosclerosis. And SOCS3 knockdown exacerbate the atherosclerotic process in apoE-/- mice by increasing the size, macrophage content and chemokines expression in the lesions. All these were accompanied by STAT1/STAT3 activation. In view of the similarities between heart valve calcification and atherosclerosis, negative regulation of JAK-STAT by SOCS seems a promising intervention for alleviating valve calcificaion. .In this project, we are aiming to investigate: whether SOCS plays a pivotal role in the pathogenesis of valve calcification by regulating inflammatory reactions through JAK-STAT signaling pathway.