STIM1突变与核浆钙信号调控

Based on the pilot experimental findings made by the applicant about STIM1 with a single point mutation in the signal peptide sequence in human umbilical vein endothelial cells of gestational hypertension patients and its translocation to perinuclear membrane upon intracellular Ca2+ depletion, the current project is to reveal the molecular mechanisms underlying mutated-STIM1 translocation to perinuclear membrane, its regulation of cytoplasm calcium-independent nuclear calcium signaling and the biological/pathological significances in CREB transcriptional activation, MMP-2 gene expression and endothelial functions. We will further affirm the universality of mutated-STIM1 translocation to perinuclear membrane and regulation of nuclear calcium signaling induced by the membrane receptor stimulation. Additionally, we will use the method detecting the wild-STIM1 and mutated-STIM1 abundance that applicant established to reveal the potential correlation between mutated-STIM1 abundance and endothelial dysfunctions of gestational hypertension patients. This project will be expected to provide new mechanisms for the regulation of nuclear calcium signaling and the pathogenesis of vascular endothelial injury.

本项目拟在申请人预实验发现妊高症患者脐静脉内皮细胞STIM1信号肽区域发生点突变以及钙储池排空诱导该突变型STIM1向细胞核膜移位的基础上，探讨突变型STIM1向核膜移位的分子机理，并进一步揭示其向核膜移位调控胞浆钙非依赖性核钙信号的机制及其发挥的生物学/病理生理学作用，包括对CREB转录激活、MMP-2基因表达和内皮细胞功能的调节等。同时，本项目将在膜受体刺激下确认突变型STIM1移位至核膜并调控胞浆钙非依赖性核钙信号的普遍性。此外，还将采用申请人已成功建立的野生型和突变型STIM1 mRNA丰度检测等方法，揭示突变型STIM1参与妊高症患者内皮损伤的相关机制。本项目的实施可望为核钙信号的调控机制以及血管内皮损伤的发病机理提供新的理论解释。

本项目在申请人预实验发现妊高症患者脐静脉内皮细胞STIM1 信号肽区域发生点突变以及钙储池排空诱导该突变型STIM1 向细胞核膜移位的基础上，探讨其向核膜移位的作用及其发挥的生物学/病理生理学意义。研究首先发现，突变型STIM1 向细胞核膜移位通过RyRs和NAADP调控胞浆非依赖性核钙信号，进而增强转录因子CREB活性，促进血管内皮细胞MMP-2基因表达和血管管腔形成，从而为突变型STIM1可能参与妊娠高血压形成提供了机制解释。