Ⅱ型谷氨酰胺转氨酶通过Wnt/beta-catenin信号通路调控主动脉瓣钙化的机制研究

项目名称： Ⅱ型谷氨酰胺转氨酶通过Wnt/beta-catenin信号通路调控主动脉瓣钙化的机制研究

项目编号： No.81470507

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 周新民

作者单位： 中南大学

项目金额： 68万元

中文摘要： 主动脉瓣退行性钙化的患病率逐年增高，其治疗方法目前仅局限于手术而缺乏有效的防治措施。近年来研究发现主动脉瓣退行性钙化属于心血管系统异位钙化，其发生发展的主要机制是主动脉瓣间质细胞向成骨样细胞分化，使得研制出有效药物防治主动脉瓣钙化成为可能。Ⅱ型谷氨酰胺转氨酶（transglutaminse2, TG2）广泛存在于生物体内，可通过wnt/β-catenin通路促进血管平滑肌细胞向成骨细胞分化而引起动脉钙化；而wnt/β-catenin信号也参与了主动脉瓣钙化的形成。本课题组前期研究发现TG2在体外可促进主动脉瓣间质细胞向成骨样细胞分化，形成钙化结节。在此基础上，本研究拟建立主动脉瓣钙化的体外细胞和体内动物模型，从细胞到整体水平来研究TG2对主动脉瓣钙化的影响机制，并初步尝试TG2抑制剂是否能够阻断其作用。本课题的研究，有助于揭示主动脉瓣钙化的发病机制，为主动脉瓣退行性钙化的防治奠定基础。

中文关键词： 心脏瓣膜病；主动脉瓣钙化；主动脉瓣狭窄；II型谷氨酰胺转氨酶；wnt/beta-catenin

英文摘要： The prevalence of degenrative aortic valve calcification(DAVC) is increasing year by year. The cure of DAVC is currently limited to surgical treatment, lack of effective preventable and treatable measures. Recent studies have viewed DAVC as ectopic calcification of cardiovascular system, in which the main mechanism is that aortic valve interstitial cells differenticate into osteoblast- like cells. This theory would contribute to the study of effective drugs which can prevent and treat aortic valve calcification. Type II transglutaminase (TG2) is widely expressed in body. It was demonstrated that TG2 can promote vascular smooth muscle cells differentiation into osteoblast-like cells and results in arterial calcification via wnt/β-catenin and wnt/β-catenin was also involved in aortic valve calcification. However, There is no evidences that demonstrate TG2 can affect aortic valular calcification currently. Our previous study found that TG2 can accelerate aortic valve interstitial cells differentiation into osteoblast-like cells and calcified nodules formation in vitro. On this basis , we intends to establish aortic valvular calcification models which contain cell model in vitro and animal model in vivo animal models in this study. The two models make us study the effects and mechanism of TG2 regulating aortic valvular calcification from cell level to organism level, and we initially try to research whether TG2 inhibitors will block this effect in the meantime. The study of this subject will help reveal the pathogenesis of aortic valve calcification and lay the foundation of prevention and treatment of DAVC.

英文关键词： cardiac valve diseases;aortic valve calcification;aortic valve stenosis;transglutaminase 2;wnt/beta-catenin