CEACAM1通过Notch1信号通路调节心房细胞代谢重构在房颤中的作用

房颤是严重威胁人类健康的疾病。高频而无序的心房电、机械活动势必引起代谢重构，以至能量供求再平衡。最新研究报道：癌胚抗原粘附分子1（CEACAM1）是胰岛素受体的底物之一，敲除CEACAM1可引起胰岛素抵抗。我们前期研究：通过高频起搏犬心房建立房颤模型，首次发现心房CEACAM1显著下调，并通过生物信息学分析提示可能涉及Notch1信号通路，但意义不清。因此我们假设：心房细胞CEACAM1下调，可能通过Notch1信号通路，导致心房代谢重构（糖酵解酶上调，糖、脂氧化酶下调）和电重构（钾、钙离子通道下调和缝隙连接蛋白上调），从而触发和维持房颤。故本申请拟：1分离和培养小鼠心房内皮细胞和平滑肌细胞，利用CRISPR/Cas9敲除CEACAM1基因；2检测代谢和电重构的关键酶、蛋白活性和表达变化；3探讨该变化是否与Notch1信号通路相关。以期率先阐明CEACAM1调控代谢重构在房颤中的作用。

Atrial fibrillation is a serious disease that threatens human health. Metabolic remodeling is an important pathophysiological mechanism in AF. Carcinoembryonic antigen-adhesive molecule 1 (CEACAM1) is one of the substrates of the insulin receptor, knocking out CEACAM1 can cause insulin resistance. In the previous study of the atrial fibrillation model of high-frequency pacing dog atrium, the expression of CEACAM1 in atrial myocytes was significantly decreased, and bioinformatics analysis suggested that Notch1 signaling pathway may be involved, but the significance and mechanism are still unclear. Therefore, we hypothesized that CEACAM1 is down-regulated in atrial myocytes, possibly through the Notch1 signaling pathway, leading to metabolic remodeling of cardiomyocytes, mitochondrial dysfunction, and ultimately phenotypic characteristics of atrial fibrillation cells. Therefore, this application will research: 1 isolation of mouse atrial endothelial cells and smooth muscle cells, knockout CEACAM1 gene using CRISPR/Cas9; 2 detection of metabolic and electrophysiological remodeling of cell phenotype; 3. explore the change Whether it is related to the Notch1 signaling pathway. To elucidate the possible mechanisms by which CEACAM1 mediates metabolism and electrophysiological remodeling in atrial cells, laying the foundation for an in-depth understanding of atrial fibrillation and exploring new therapeutic targets.