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（由申请人提供）：在人类心脏中，成孔 KCNQ1（KV7.1；Q1）亚基与辅助 KCNE1（E1）亚基组装形成缓慢激活的延迟整流钾电流 IK，这对正常心脏至关重要动作电位 (AP) 复极化 心脏 IK 的减少会延长心室动作电位持续时间 (APD)，从而导致较长时间。 QT 综合征 (LQTS) 是一种容易引发劳力引发的致命性心律失常和心源性猝死 (SCD) 的疾病，在美国每年约有 40 万例 SCD 病例中，LQTS 占很大一部分，影响从婴儿到成年人的所有年龄段。目前的 LQTS 治疗方案（β 受体阻滞剂治疗、植入式除颤器、左心交感神经去神经术）并不能纠正潜在的复极异常，而且都具有治疗效果。心脏 IK 的病理性降低可能是由于通道亚基（Q1─LQT1；E1─LQT5）的遗传突变引起的，也可能是在衰竭的心脏中获得的，可能是这种情况下不利的神经激素环境的结果。从机制上讲，心脏 IK 减少可能是由于：(i) 通道亚基组装不当；(ii) Q1 和/或 E1 亚基向心脏细胞表面的运输减少； (iii) 表面通道的异常生物物理特性（包括通道激活电压依赖性的 Po 减少和右移）；以及 (iv) 大多数心脏 IK 密度和/或功能调节降低的精确分子机制。遗传性和获得性 LQTS 的病例尚不清楚，这种清晰度的缺乏是针对这种危险病症合理开发新疗法的关键障碍。导致缺乏进展的因素包括：(1) IK 不存在，并且不会导致动作电位复极化。在常用的（2）缺乏定量的小鼠模型； 监测心脏中的动态 IK 通道运输；(3) 缺乏直接研究 LQT1 突变对成人心肌细胞功能影响的研究。我们的长期目标是阐明控制心脏中 Q1/E1 通道的表面密度和功能调节的分子机制。我们已经做出了多项创新来推进这些目标，包括开发测量光学工具。活细胞中的 Q1/E1 组装、表面密度和动态运输，并建立两个互补的成体培养心肌细胞模型系统来直接阐明心脏细胞中的 LQT1 机制：（1）利用光学方法来阐明控制表面的机制。 (2) 阐明 Q1 C 末端的不同 LQT1 突变损害成人心室心肌细胞 IK 功能的机制。 (3) 确定心力衰竭时长期升高的蛋白激酶对心脏 Q1/E1 表面密度、运输、功能和调节的影响。