MOLECULAR PHYSIOLOGY OF LONG QT SYNDROME & IDIOPATHIC VENTRICULAR FIBRILLATION

长 QT 综合征的分子生理学

• 批准号: 6576586
• 负责人: Michael Craig Sanguinetti
• 金额: $ 20.67万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576586
• 关键词: Xenopus; Xenopus oocyte; antiarrhythmic agent; cardiac myocytes; gene mutation; genetic disorder; heart electrical activity; heart pharmacology; laboratory rabbit; long QT syndrome; membrane channels; membrane potentials; potassium channel; sodium channel; sudden cardiac death; ventricular fibrillation; voltage /patch clamp

The long-term goals of this project are to understand the molecular basis of channel dysfunction caused by mutations in ion channel genes that cause cardiac arrhythmia, and to explore potential therapies at the cellular and organ level based on these findings. Subproject 1 will explore the mechanism of action and normalization of cardiac repolarization by an activator of KvLGT1 and cardiac I/Ks channels. A novel benzodiazepine (R-L3) was recently discovered that increases the magnitude of I/Ks and shortens action potential duration. We will study the effects of this compound on KvLGT1 and minK channel subunits heterologously expressed in Xenopus oocytes. We will also determine if this compound can suppress early after depolarizations in rabbit myocytes and prevent torsades de pointes in isolated perfused hearts. Subproject 2 will investigate the biophysical properties of mutations in SCN5A that cause long QT syndrome and idiopathic ventricular fibrillation. Gating and ionic currents recorded from sodium channels heterologously expressed in cultured mammalian cells will be used to understand abnormal channel function of SCN5A mutations. Subproject 3 will characterize mutations in HERG and newly discovered genes that cause long QT syndrome that are identified in Project 1. These studies will utilize both the oocyte and cultured mammalian cell expression systems. We will initially concentrate on mutations in HERG that will provide insights into the structural basis of channel function.

该项目的长期目标是了解引起心律不齐的离子通道基因突变引起的通道功能障碍的分子基础，并根据这些发现探索细胞和器官水平的潜在疗法。 subproject 1将探索通过KVLGT1和心脏I/KS通道的激活剂对心脏复极化的正常化机理。最近发现一种新型的苯二氮卓（R-L3）增加了I/KS的幅度并缩短了动作潜在持续时间。我们将研究该化合物对在异武肠卵母细胞中异源表达的KVLGT1和Mink通道亚基的影响。我们还将确定这种化合物在兔肌细胞中去极化后是否可以尽早抑制，并防止扭转尖锐的刺激性刺激性灌注的心脏。 subproject 2将研究SCN5A突变的生物物理特性，这些特性会导致长QT综合征和特发性心室纤维化。从培养的哺乳动物细胞中异源表达的钠通道记录的门控和离子电流将用于了解SCN5A突变的异常通道功能。 Subproject 3将表征HERG和新发现的基因，这些突变引起了项目1中鉴定出的长QT综合征。这些研究将同时利用卵母细胞和培养的哺乳动物细胞表达系统。我们最初将集中于HERG中的突变，这些突变将提供对信道功能的结构基础的见解。