心房颤动机制研究进展--细胞核孔复合物与跨核运输障碍.ppt

心房颤动机制研究进展 -细胞核孔复合物与跨核运输障碍,/sundae_meng,故事的开始： 常染色体隐性遗传房颤家系,/sundae_meng,-57 family members -32 males -25 females -5 living generations -Age: 3 m-93 y -Autosomal recessive inheritance pattern -7 consanguineous marriages,An Interesting Family,Circulation, 2004,/sundae_meng,Oberti et al. Circulation, 2004;110:3753-3759,Proband V:11 -Chronic AF -QTc=0.42 s -Delivered by caesarean section due to fetal tachycardia, HR of 250 bpm, atrial fibrillation and atrial flutter -Echo at day 2: marked dilatation of both atria, EF 52% -EP at 1 m detected AF, ablation of AV node -Pacemaker Echo at 2 m: mild atrial dilatation, normal EF 52% -Died suddenly at 15 m,/sundae_meng,Oberti et al. Circulation, 2004;110:3753-3759,Patient VI:2 -Chronic AF -QTc=0.40 s -HR=125 bpm with digoxin and propafenone Echo at 15 m: normal -Died suddenly at 19 m,/sundae_meng,Oberti et al. Circulation, 2004;110:3753-3759,Patient V:9 -Atrial flutter - Delivered by C section due to fetal tachycardia -Born with supraventricular tachycardia -ECG at 24 d: atrial flutter, HR=200 bpm -Echo at 24 d: normal -Later Echo: mild dilatation of left ventricle and left atria -Died suddenly at 3 m,/sundae_meng,Oberti et al. Circulation, 2004;110:3753-3759,Patient V:10 -Born with atrial tachycardia -Echo : normal -Died suddenly at 2 m,Patient VI:1 -Born with atrial tachycardia -Electrical conversion at 20 d -Echo at 1 m: normal -Died suddenly at 18 m,Patient VI:3 -Born with AF and atrial tachycardia on Feb. 14, 2007 -In sinus rhythm on propafenone, propranolo, aspirin,Family member IV:17 and IV:18: -died suddenly,/sundae_meng,是什么导致了此家系中早发、恶性房颤？,/sundae_meng,连锁分析,Circulation, 2004,/sundae_meng,NUP155突变R391H,/sundae_meng,NUP155,核孔复合体（nuclear pore complex）主要成分,/sundae_meng,核孔复合体负责大分子物质在细胞核与细胞质之间转运,/sundae_meng,如何进一步证实NUP155突变可以导致房颤？,/sundae_meng,NUP155 基因敲除小鼠,NUP155-/-小鼠在胚胎期8.5天内死亡 NUP155+/-小鼠中NUP155蛋白的心肌表达量减半,/sundae_meng,NUP155 +/- 小鼠,阵发性房颤,/sundae_meng,Induced AF in NUP155 +/- KO Mice,WT,NUP155+/- KO,AF,Irregular RR,/sundae_meng,NUP155突变如何导致房颤？,/sundae_meng,影响Hsp70 mRNA转运出核-影响Hsp70蛋白质转运入核,NUP155缺陷(突变与表达下调),Hsp70,Hsp70,/sundae_meng,心房肌细胞动作电位时长变短,NUP155 +/- 小鼠,/sundae_meng,What is the mechanism for APD shortening in NUP155+/- KO mice?,/sundae_meng,Increased IK1 Current in NUP155 KO Cardiomyocytes,/sundae_meng,Increased Kir2.1 Expression in NUP155 KO Mice,/sundae_meng,Stress,/sundae_meng,结论,第一隐性房颤伴猝死基因发现 第一次将核孔复合体联结到心血管疾病 关于非离子通道基因导致房颤的第一报道 发现一崭新的控制或治疗房颤的药靶 核孔复合体蛋白NUP155突变可以在人和动物中导致房颤 NUP155突变通过影响蛋白质的核转入及mRNA的核输出导致房颤 NUP155突变通过缩短心房细胞动作电位间期,可能引起reentry导致房颤 NUP155突变通过增加Kir2.1 表达和IK1 钾电流,缩短心房细胞动作电位间期,/sundae_meng,华中科大博士研究生张贤钦以第一作者在国际顶尖学术杂志 Cell发表论文,细胞出版社专门做了新闻发布、世界几百家媒体，包括美国，中国，日本，南韩，比利时等国新闻单位，都做了报道,房颤与猝死致病新基因发现,/sundae_meng,致 谢,华中科技大学生命科学与技术学院人类基因研究中心CARDIO-X团队 教师：凃欣、石立松、任翔、柯铁、李辉、李先涛 博士生：李聪、王鹏云、汪樊、徐承启、王楚楚 李修春、王丹、熊欣 CARDIO-X团队其他同学,/sundae_meng,致 谢,杨延