FGF-23参与心房颤动发生的作用及机制研究

近期多项研究表明，血浆成纤维细胞生长因子23（FGF23）水平升高，患者心房颤动（房颤）发生风险增加30-60%。FGF23可以干扰心肌细胞正常钙调节，导致钙稳态失调，从而促发心律失常，但具体分子调控机制尚不明确。申请者前期研究显示FGF23可以增加心房组织钙调蛋白依赖激酶Ⅱ（CaMKⅡ）活性，而CaMKⅡ通道导致的心肌自发性钙漏是房颤发生的重要病理生理机制。因此，我们提出FGF23可激活心肌激酶通道，通过CaMKⅡ钙调控轴引起心肌钙稳态失调导致房颤的假说。本研究将以小鼠为模型，从动物、组织及细胞三个层次，首先探索FGF23对小鼠在体心脏电生理及心房结构功能的影响，然后探讨FGF23对小鼠心肌细胞电生理及钙转运功能的作用，并进一步明确FGF23导致心房肌钙稳态失调的分子调控信号通路。本研究将明确FGF23致房颤的电生理及分子信号调控机制，为房颤的上游预防及早期干预提供新的靶点和理论依据。

High circulating fibroblast growth factor 23 (FGF23) concentration is a newly recognized and strong predictor of incident atrial fibrillation (AF). Recent studies showed that FGF23 increased arrhythmogenesis with calcium dysregulation in atrial cells and pulmonary vein cardiomyocytes. However, the underlying molecular mechanism remains unclear. Our previous work demonstrated that FGF23 increased CaMKⅡ activity in the atrium, and subsequently resulted in calcium handling disorder in atrial myocytes. Calcium dysregulation through activation of CaMKⅡ is the main pathophysiological mechanism of AF. Therefore, we hypothesize that FGF23 promotes the development of AF by activating some cardiac kinases through CaMKⅡ mediated calcium dysregulation pathway. In this study, we aim to 1) investigate the effect of FGF23 on the AF inducibility and atrial structural remodeling in mice; 2) investigate the electrophysiological effects of FGF23 on calcium hemostasis in atrial myocytes; 3) investigate the kinases activation and molecular mechanism of FGF23 induced AF through CaMKⅡ pathway in the atrium. This study will clarify the electrophysiological and molecular mechanism of FGF23 induced AF, and provide evidence of a novel therapeutic target for upstream prevention and early intervention of atrial fibrillation.