钙敏感受体(CaSR)作为调控细胞内外钙平衡的感受器近年来受到广泛关注，但其在肝脏疾病特别是肝纤维化中的作用国内外未见报道，我们预实验结果提示CaSR在肝纤维化的进程中具有保护作用，CaSR首先通过PLC-IP3途径介导活化的肝星状细胞(HSC)内质网钙库倾空，Ca2+代谢失衡激活了细胞的内质网应激过程，而HSC的活化导致回补内质网钙库的关键钙通道SOCC(STIM1/TRPC1复合体)功能的下降，介导的外钙内流减少，最终使得内质网应激持续存在，并通过下游PERK-eIF2α-ATF4-CHOP信号通路引起凋亡级联反应，加速活化的HSC细胞的凋亡，抑制肝纤维化的发生。本课题从CaSR和细胞内质网应激的角度阐述了HSC细胞凋亡调控的新机制，为以HSC凋亡为治疗策略的靶向药物研发开辟了新的方向，并同时为临床上倡导的肝纤维化病人适当补钙提供了理论依据.

Calcium-sensitive receptors (CaSRs) as receptors regulating intracellular and extracellular calcium homeostasis have attracted wide attention in recent years. But its role in liver diseases, especially in liver fibrosis, has not been explored. Our preliminary study found that CaSR has a protective role in the progression of liver fibrosis. PLC-IP3 pathway mediates the emptying of the calcium pool in endoplasmic reticulum (ER) in activated hepatic stellate cells (HSCs), and the dysregulation of calcium homeostasis activates endoplasmic reticulum stress (ERS). The activation of HSCs also induces attenuation of the function of SOCC (STIM1/TRPC1 complex), the calcium channel responsible for replenishment of the calcium pool in ER, and thus reduction of external calcium influx. These responses ultimately lead to persistence of ERS, and induces apoptotic cascade through the downstream PERK-eIF2a-ATF4-CHOP signal pathway, hence accelerating the apoptosis of activated HSC cells, and inhibiting the occurrence of liver fibrosis. This proposal aims to reveal a new mechanism of HSCs apoptosis regulation from the CaSR and ERS, provide a new direction for the research and development of theurapeutics with HSC apoptosis as the target, and also provide a theoretical basis for proper calcium supplementation advocated clinically in patients with hepatic fibrosis.