FoxO3及其非编码调控在心脏术后房颤中的功能和机制研究

心房颤动（房颤）在心脏手术后的发生率高达20-60%，严重影响患者的生存及预后，但其发生机制仍未阐明。证据表明高龄是术后房颤发生最重要的危险因素之一，我们在前期研究中发现，年龄相关分子FoxO3的表达与术后房颤有着负性关系。FoxO3在心肌细胞损伤与保护、增殖与死亡、肥大与萎缩等多个稳态中发挥着重要的平衡作用，除受其编码基因的调控外，它还受到来自于多种信号的非编码调控，如circularRNA、假基因、microRNA等。依据最新研究和预实验结果，我们提出以下假说：FoxO3与心脏术后房颤有一定的相关性，其非编码调控在其中扮演着重要角色。为验证假说，本项目选择临床、动物、细胞三个层面研究FoxO3蛋白及相关基因与房颤的关系，并通过基因编辑的手段，观察其编码及非编码调控对房颤的影响。本项目旨在进一步揭示术后房颤发生的新机制，并为该病的防治提供重要的理论基础及干预靶点。

Atrial fibrillation (AF) is one of the most common complications after cardiac surgery, but its mechanism is still unclear. In preliminary study, we found FoxO3 and related gene regulation maybe involve in the mechanism of postoperative AF. The latest research shows that: FoxO3 was affected by its upstream signaling pathway (AKT and PTEN) and non-coding gene (miRNA, circRNA, and pseudo-gene) regulation. According to the latest research progress and results of preliminary experiments, we raise a scientific hypothesis that FoxO3 and related gene regulation affect the atrial fibrosis and AF vulnerability. In order to verify the hypothesis, this study aims to select clinical specimens, dog AF model, atrial fibroblasts model; using gene transfection, gene transfer and gene knockout technology; realizing overexpression and inhibition of FoxO3 mRNA、circ-FoxO3、FoxO3 pseudo-gene expression; Observing the effect of FoxO3 on atrial fibrosis and AF vulnerability by using the method of electrophysiology, morphology and molecular biology; to clarify the effect and molecular mechanism that FoxO3 and related gene regulation affect the atrial fibrosis and AF vulnerability, in vitro and in vivo experiment, different levels and perspectives. This study may provide new insights into the underlying mechanisms of postoperative AF and provide potential novel mechanism-based therapeutic strategies for AF.