Mechanisms of Long QT Syndrome 1 in Heart

心脏长 QT 综合征 1 的机制

• 批准号: 9038483
• 负责人: Henry M. Colecraft
• 金额: $ 44.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038483
• 关键词: A kinase anchoring protein; Accounting; Action Potentials; Address; Adult; Affect; Arrhythmia; Binding; Biological Models; Calmodulin; Cardiac; Cardiac Myocytes; Cavia; Cell surface; Cells; Chronic; Complex; Data; Dependence; Development; Disease; Elderly; Endocytosis; Exertion; Fluorescence Resonance Energy Transfer; Glucocorticoids; Heart; Heart failure; Hormonal; Human; Image; Implantable Defibrillators; Infant; Inherited; Label; Left; Life; Long QT Syndrome; Maps; Measures; Modeling; Molecular; Monitor; Muscle Cells; Mutation; Optics; Patients; Phosphotransferases; Physiological; Potassium; Protein Kinase; Proteins; Quantum Dots; Rattus; Regulation; Risk; Romano-Ward Syndrome; Serum; Surface; Sympathectomy; Testing; Therapeutic Intervention; Time; United States; Ventricular; Ventricular Arrhythmia; adenylate kinase; adverse outcome; age group; base; biophysical analysis; biophysical properties; density; genetic regulatory protein; heart cell; innovation; insight; mouse model; novel therapeutics; personalized medicine; protein expression; public health relevance; sudden cardiac death; tool; trafficking; voltage

 DESCRIPTION (provided by applicant): In human heart, pore-forming KCNQ1 (KV7.1; Q1) subunits assemble with auxiliary KCNE1 (E1) subunits to form the slowly activating, delayed rectifier potassium current, IKs, which is essential for normal cardiac action potential (AP) repolarization. Decreased cardiac IKs prolongs the ventricular action potential duration (APD), resulting in long QT syndrome (LQTS), a disorder that predisposes to exertion-triggered fatal arrhythmias and sudden cardiac death (SCD). LQTS accounts for a significant portion of ~400,000 cases of SCD in the United States each year affecting all age groups from infants to the elderly. Current treatment options for LQTS (β- blocker therapy, implantable defibrillators, left cardiac sympathetic denervation) do not correct the underlying repolarization abnormality and all have significant limitations. Pathological decreases in cardiac IKs can arise due to inherited mutations in channel subunits (Q1─ LQT1; E1─ LQT5), or can be acquired in the failing heart, potentially as a consequence of the adverse neuro-hormonal milieu in this condition. Mechanistically, reduced cardiac IKs may be due to: (i) improper assembly of channel subunits; (ii) diminished trafficking of Q1 and/or E1 subunits to the heart cell surface; (iii) abnormal biophysical properties of surface channels (including diminished Po and rightward shifts in voltage-dependence of channel activation); and (iv) impaired sympathetic regulation. The precise molecular mechanisms underlying reductions in cardiac IKs density and/or functional regulation in most cases of inherited and acquired LQTS is unknown. This lack of clarity is a critical barrier to rational development of new therapies for this dangerous condition Factors contributing to the lack of progress are: (1) IKs is absent and does not contribute to action potential repolarization in popularly used mouse models; (2) lack of tools to quantitatively monitor dynamic IKs channel trafficking in heart; and (3) paucity of studies investigating functional impact of LQT1 mutations directly in adult cardiomyocytes. Our long term objective is to elucidate the molecular mechanisms controlling the surface density and functional regulation of Q1/E1 channels in heart under both physiological and pathological conditions, and to bridge the mechanistic insights to advance personalized therapy for LQTS and life-threatening cardiac arrhythmias. We have made several innovations to advance these objectives including developing optical tools to measure Q1/E1 assembly, surface density, and dynamic trafficking in live cells, and establishing two complementary adult cultured cardiomyocyte model systems to elucidate LQT1 mechanisms directly in heart cells. We propose three specific Aims: (1) Utilize optical approaches to illuminate mechanisms controlling surface density of Q1/E1 channel complexes in heart. (2) Elucidate mechanisms by which distinct LQT1 mutations in Q1 C-terminus impair IKs function in adult ventricular cardiomyocytes. (3) Determine the impact of protein kinases that are chronically elevated in heart failure on Q1/E1 surface density, trafficking, function, and regulation in heart.

 描述（由适用提供）：在人心脏中，孔形成KCNQ1（KV7.1; Q1）亚基与辅助KCNE1（E1）亚基组装，形成缓慢激活的，延迟的整流性钾钾电流，IKS，IKS，IKS，这对于正常的心脏动作电位（AP）重复极化至关重要。降低心脏IK会延长心室动作电位持续时间（APD），导致QT综合征（LQTS）长期，这种疾病易于劳累触发的致命性心律不齐和心脏猝死（SCD）。 LQTS每年在美国占约400,000例SCD案例，影响了从婴儿到老年人的所有年龄段。当前的LQT（β受体阻滞剂治疗，可植入的除颤器，左心交感神经去神经）的治疗方案均不纠正潜在的重复性绝对化，并且都有显着的局限性。心脏IK的病理下降可能是由于在这种情况下在这种情况下，由于不良神经荷尔蒙环境而导致的，可能是由于心脏失败的心脏中遗传突变（Q1- LQT1; E1- LQT5）引起的。从机械上讲，减少的心脏IK可能是由于：（i）通道亚基的不当组装； （ii）Q1和/或E1亚基的运输减少到心脏细胞表面； （iii）表面通道的异常生物物理特性（包括PO降低和通道激活电压依赖性的向右移动）； （iv）交感神经调节受损。在大多数遗传和获得的LQT中，心脏IKS密度和/或功能调控的确切分子机制尚不清楚。缺乏明确性是对这种危险条件因素的合理发展的关键障碍，导致缺乏进步的危险条件因素是：（1）IKs不存在，并且在常用的小鼠模型中没有促进行动潜在的重复化； （2）缺乏定量的工具 监控动态IKS频道在心脏中贩运； （3）缺乏研究直接在成人心肌细胞中LQT1突变的功能影响的研究。我们的长期目标是阐明控制心脏和病理条件下Q1/E1通道的表面密度和功能调节的分子机制，并弥合机械见解以推动LQT和生命威胁性心脏的个性化治疗的机械见解，我们已经促进了几个创新，包括在Q1/E1组成的Q1/E1组成的Q1/E1组成，并建立了Q1/E1的动态工具，并促进了Q1/E1的汇集，并构建了E1/E1的汇集，并促进了Q1/E1的组装，并促进了Q1/E1的组装，并促进了E1/E1的汇集，并促进了Q1/E1的整理，并促进了Q1/E1的启发，并促进了Q1/E1的整理，并促进了Q1/E1 contrand andermend and的动态工具。完整的成年培养的心肌细胞模型系统，以直接阐明心脏细胞中的LQT1机制。我们提出了三个具体目的：（1）利用光学方法来阐明控制Q1/E1通道复合物的表面密度的机制（2）阐明机制，通过这些机制，Q1 C-末端在成人心室心肌细胞中造成了不同的LQT1突变。 （3）确定心力衰竭对Q1/E1表面密度，运输，功能和心脏调节的蛋白激酶的影响。