增龄是心房颤动（AF）发生的独立危险因素。老龄化导致AF发病率急剧上升，但治疗困难，新的防治靶点亟待挖掘。细胞凋亡和心房纤维化是增龄性AF始动因素。干细胞移植促进心肌细胞再生、抑制纤维化，但存在免疫排斥和致瘤等诸多问题。预实验显示iPSC来源外泌体（iPSCexo）显著抑制增龄性心房纤维化和AF易损性。联合高通量测序和生物信息学筛选出调控纤维化和AF的关键iPSCexo miRNAs，并预测Egr-1/Agrin为其靶基因显著性富集信号通路。而且，iPSCexo可以调控小鼠心房组织Egr-1和Agrin增龄性改变。因此，本课题拟采用心肌Egr-1和AGRN条件性敲除和慢病毒载体技术，应用电生理学、生物信息学、形态学及分子生物学等，深入探讨iPSCexo miRNAs通过调控Egr-1/Agrin通路抑制增龄性心房重构和AF作用机制，为进一步探索防治增龄性AF新靶点提供实验依据和理论指导。

Aging is the independent determinant of atrial fibrillation (AF) occurrence, and the prevalence of AF is sharply increasing with the aggravating trend of aging population. Prevention and treatment of AF is so difficult. Consequently, it is so urgent to explore new therapeutic approaches for age-related AF. Apoptosis and atrial fibrosis are the initial factors of age-related AF. Stem cell transplantation contributes to cardiomyocytes proliferation and inhibits fibrosis, but the challenges of immune rejection and the tumorigenesis consideration remain unsolved. Pilot study revealed that induced pluripotent stem cells-derived exosomes (iPSCexo) considerably inhibit age-related atrial fibrosis and AF vulnerability. We identified the iPSCexo miRNAs related to fibrosis and AF and then recognized Egr-1/Agrin pathway as the target genes for the miRNAs by high-throughput sequencing and bioinformatics. And iPSCexo could modulate the expression level of egr-1 and agrin in aged mouse. So, in the present project, conditional knockout and transgenic lentiviral vector of Egr-1 and Agrn, electrophysiology, bioinformatics, morphology and molecular biology will be used to explore the roles and mechanisms of iPSC-derived exosomal miRNAs on age-related atrial remodeling and AF via targeting Egr-1/Agrin pathway.The present project will further help reveal the new target in the prevention and treatment of age-related AF.