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,华中科技大学生命科学与技术学院华中科技大学人类基因组研究中心分子生物物理教育部重点实验室王擎,故事的开始：常染色体隐性遗传房颤家系,2,-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,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,Oberti et al.Circulation,2004;110:3753-3759,Patient VI:2-Chronic AF-QTc=0.40 s-HR=125 bpm with digoxin and propafenoneEcho at 15 m:normal-Died suddenly at 19 m,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,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,是什么导致了此家系中早发、恶性房颤？,连锁分析,9,Circulation,2004,NUP155突变R391H,10,NUP155,核孔复合体（nuclear pore complex）主要成分,11,核孔复合体负责大分子物质在细胞核与细胞质之间转运,如何进一步证实NUP155突变可以导致房颤？,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,14,NUP155+/-小鼠,阵发性房颤,15,Induced AF in NUP155+/-KO Mice,WT,NUP155+/-KO,AF,Irregular RR,NUP155突变如何导致房颤？,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,心房肌细胞动作电位时长变短,19,NUP155+/-小鼠,What is the mechanism for APD shortening in NUP155+/-KO mice?,Increased IK1 Current in NUP155 KO Cardiomyocytes,Increased Kir2.1 Expression in NUP155 KO Mice,23,Stress,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,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,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,致 谢,杨延宗，夏云龙，刘颖，刘金秋（大连医科大学）廖玉华，程翔（华中科技大学同济医学院附属协和医院心内科）杨宝峰（哈尔滨医科大学）杨波，吴钢，黄从新（湖北省人民医院）吴艳霞，柯于鹤（武汉市第一医院）,Thank you！,
