流行病学分析表明：肿瘤与房颤（AF）发生密切相关。人食道癌相关基因4（Ecrg4）具有抑制炎症和细胞增殖反应的功能。Ecrg4在房室结及心房高表达；HL1细胞经电刺激后，Ecrg4表达明显降低。我们前期研究发现（1）Ecrg4在心脏传导系统高表达；（2）AF患者心耳及犬AF模型心房，Ecrg4表达明显降低；（3）敲低乳鼠心房肌细胞Ecrg4后，动作电位时程明显缩短。因此我们假说：Ecrg4在AF发生和发展中起重要的作用。本研究拟运用Cre-LoxP技术构建心脏特异性Ecrg4敲除大鼠，观察大鼠自发AF、和对运动及快速心房起搏诱发AF的易感性；利用实时PCR和ELISA分析炎性因子及心房重构相关分子的表达；利用IHC分析心房炎性细胞浸润和纤维化。然后，经逆向冠脉灌流恢复Ecrg4的表达，观察其对AF的预防和治疗作用。从而阐明Ecrg4在AF发生中的作用及机理，为AF的治疗提供理论基础和靶点。

Accumulating epidemiological evidence has shown that atrial fibrillation (AF) and tumor are closely correlated; however the molecular link underlying the correlation remains to be explored. Esophageal cancer related gene-4 (Ecrg4), originally characterized as a tumor suppressor gene, functions as a ‘sentinel’ molecule monitoring tissue homeostasis: presence of Ecrg4 signals homeostasis, whereas loss of which activates inflammation and tissue proliferation. It has been shown that Ecrg4 is highly expressed in atrioventricular(A-V) node, and that HL1 cells express significantly lower level of Ecrg4 after a 24-hour of rapid electrical stimulation, suggesting a potential role of Ecrg4 in atrial electrical remodeling. Our preliminary data have shown that expression of Ecrg4 is higher in both atria and conduction systems than ventricles in rat; that atrial appendages in patients with AF showed significantly decreased Ecrg4 expression compared to their counterparts in Sinus rhythm; that expression of Ecrg4 in atria was significantly down-regulated in a canine AF model; and that knockdown Ecrg4 in neonatal rat atrial myocytes significantly shortened action potential duration. Therefore， we propose that Ecrg4 play a critical role in the pathogenesis of AF. Here we plan to create a heart-specific Ecrg4 knockout （KO） rat using the Cre-LoxP systems. The susceptibility to AF will be analyzed in the KO at resting, after forced exercise and rapid atria pacing; the expression of proinflammatory cytokines and molecules commonly involved in atrial remodeling will be analyzed by real-time PCR and ELISA; and the electrical and structural remodeling of atria will be analyzed by patch-clamping in isolated atrial myocytes and immunohistochemistry respectively. Then expression of Ecrg4 in the heart will be restored using inverse coronary artery reperfusion of a lentivirus expressing Ecrg4, and the therapeutic effect will be evaluated by analyzing the aforementioned variables. If confirmed, this proposal will further enhance our knowledge in the pathogenesis of AF and provide a therapeutic target for AF.