我们已经证明：功能矫形力作用下颌面部骨骼肌的成肌细胞凋亡受到CRT介导内质网应激的调控。但持续应力刺激如何导致CRT过表达和内质网应激？学者认为CRT的表达水平与胞内钙离子稳态密切相关。细胞质膜钙泵(PMCA1)是将胞内钙离子排出细胞的主要离子泵之一。预实验发现：成肌细胞中钙离子浓度与应力刺激作用的时间正相关；应力刺激导致成肌细胞中PMCA1表达水平下降。鉴于PMCA1与CRT可以通过不同的信号通路调控彼此的表达，据此推测：持续应力刺激作用下，成肌细胞中PMCA1表达的下降与CRT表达的升高通过正反馈调控而相互促进，造成二者平衡的打破与钙离子稳态的失衡，最终引起CRT介导下内质网应激和细胞凋亡。本项目拟采用细胞基因转染、基因敲除小鼠等体内外实验方法，旨在证明PMCA1与CRT的正反馈调控在持续应力刺激诱导成肌细胞凋亡中的重要作用，并探索其分子机制，为临床功能矫形治疗提供理论依据和矫治思路。

We have already proved that orthopedic mechanical force can induce myoblast apoptosis of maxillofacial skeletal muscle, which is orchestrated by CRT-mediated endoplasmic reticulum stress. But how could persistent stretch stimulation promote the overexpression of CRT and ER stress? Scholars agree that the level of CRT is closely related with calcium homeostasis. Plasma membrane calcium pump 1 (PMCA1) is one of the major calcium pump that could pump the calcium out of the cells. Our previous experiments have found that the intracellular calcium concentration is positively correlated with the duration of stretch; Besides, the level of PMCA1 was decreased in myoblasts under stretch stimulation. Based on some conclusions that PMCA1 and CRT could modulate the expression of each other, we speculated that the unregulated CRT level and downregulated PMCA1 level in stretched myoblasts could be promoted by the positive feedback mechanism between the two factors. The imbalance between the two calcium related protein lead to breaking down of calcium homeostasis. This finally result in the CRT-mediated endoplasmic reticulum stress and apoptosis of myoblasts. The present program intends to use some in vitro and in vivo techniques such as overexpressing/knocking down target genes and target genes knocking-out mice, in order to prove that the positive feedback mechanism between PMCA1 and CRT is critical in persistent stretch-induced apoptosis of myoblasts, and to explore the possible molecular mechanism. The current study could provide theoretical evidences and new ideas on clinical orthopedic treatment.