Polyunsaturated fatty acids as anti-arrhythmic agents.

多不饱和脂肪酸作为抗心律失常剂。

基本信息

批准号：
10874097
负责人：
Derek Michael Dykxhoorn
金额：
$ 5.8万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-10 至 2023-07-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10874097
关键词：
Action Potentials Animal Model Animals Anti-Arrhythmia Agents Aromatic Amino Acids Arrhythmia Binding Binding Sites Calcium Channel Cardiac Cardiac Myocytes Cells Cessation of life Child Clinical Clinical Trials Computer Simulation Computers Data Defect Dependence Development Electrocardiogram Electrodes Exhibits Family Future Heart Human In Vitro Individual Inherited Length Long QT Syndrome Membrane Potentials Molecular Molecular Mechanisms of Action Movement Mutation Oryctolagus cuniculus Patients Pharmaceutical Preparations Pharmacologic Substance Polyunsaturated Fatty Acids Potassium Potassium Channel Prevention Property Research Personnel Risk Factors Site-Directed Mutagenesis Sodium Channel Structure System Techniques Testing Transgenic Animals Transgenic Model Transgenic Organisms Variant Ventricular Ventricular Fibrillation data modeling efficacy testing experimental study functional restoration in vivo induced pluripotent stem cell derived cardiomyocytes insight novel novel therapeutics personalized medicine preclinical study prevent sensor simulation sudden cardiac death voltage voltage clamp young adult

项目摘要

Project Summary The cardiac action potential is primarily generated by sodium and calcium channels, which depolarize the membrane potential, and by potassium channels that repolarize the membrane potential and terminate the action potential. One of the major cardiac potassium currents is the slowly activating potassium current IKs that contribute to the action potential termination. Over 300 different inherited mutations have been found in IKs channels that cause cardiac arrhythmias in patients. IKs channels regulate the length of the cardiac contraction and mutations that decreases the activity of IKs channels result in a prolongation of the cardiac contraction, leading to Long QT Syndrome. In turn, Long QT syndrome is a risk factor for ventricular fibrillation and sudden cardiac death. We have identified a family of compounds that activate IKs channels and are antiarrhythmic when applied to cardiomyocytes. We will here test whether these compounds restores the length of the action potential in human cardiomyocytes from Long QT Syndrome patients. We will also test the effect of these compounds on in ex vivo animal hearts and in vivo in transgenic animals with Long QT Syndrome mutations, in order to develop drug that restores the QT interval and that can be tested in future clinical trial. We will also test variants of these compounds on heterologously expressed IKs channels using two-electrode voltage clamp, to determine the important structure of these compounds for their effects on IKs channels. We will also make mutations of IKs channels to determine the binding site of these compounds. Finally, we will test the efficacy of these compounds to reverse different defects in IKs channels caused by different types of Long QT syndrome mutations. This will be tested both in heterologous systems and in human cardiomyocytes. The anticipated results of these experiments will provide proof-of-concept that this family of compounds can shorten the cardiac action potential and prevent cardiac arrhythmia, and will provide preliminary animal model data to start clinical trials of these compounds. We anticipate that this development of new anti-arrhythmic drugs will lead to better treatments of cardiac arrhythmias and the prevention of sudden cardiac deaths in LQTS patients.

项目概要心脏动作电位主要由钠通道和钙通道产生，它们使心脏去极化膜电位，并通过钾通道使膜电位复极化并终止动作电位。主要的心脏钾电流之一是缓慢激活的钾电流 IK，有助于动作电位的终止。 IK 中已发现超过 300 种不同的遗传突变引起患者心律失常的通道。 IKs 通道调节心脏收缩的长度降低 IK 通道活性的突变会导致心脏收缩时间延长，导致长QT综合征。反过来，长 QT 综合征是心室颤动和突发性猝死的危险因素。心源性死亡。我们已经鉴定出一系列可激活 IK 通道并具有抗心律失常作用的化合物当应用于心肌细胞时。我们将在这里测试这些化合物是否可以恢复作用的长度长 QT 综合征患者的人类心肌细胞的潜力。我们也会测试一下这些的效果化合物对离体动物心脏和具有长QT综合征突变的转基因动物的体内作用，为了开发恢复 QT 间期的药物，并可以在未来的临床试验中进行测试。我们也会使用两电极电压钳在异源表达的 IK 通道上测试这些化合物的变体，确定这些化合物对 IK 通道影响的重要结构。我们还将制作 IK 通道的突变以确定这些化合物的结合位点。最后我们来测试一下效果这些化合物可逆转由不同类型的长 QT 综合征引起的 IK 通道的不同缺陷突变。这将在异源系统和人类心肌细胞中进行测试。预计的这些实验的结果将提供概念证明，即该化合物家族可以缩短心脏动作电位和预防心律失常，并将提供初步的动物模型数据以启动这些化合物的临床试验。我们预计新的抗心律失常药物的开发将导致更好地治疗心律失常并预防 LQTS 患者心源性猝死。