Novel ion channel approaches to reentrant arrythymias

治疗折返性心律失常的新型离子通道方法

基本信息

批准号：
8274331
负责人：
IRA S COHEN
金额：
$ 73.25万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8274331
关键词：
Ablation Accounting Action Potentials Adenoviruses Adult Affect Animal Model Animals Arrhythmia Canis familiaris Cardiac Cardiac Myocytes Catheters Cell Line Cell Therapy Cells Cessation of life Clinical Trials Computer Simulation Coronary Devices Engineering Frequencies Functional disorder Generations Genes Genetic Goals Head Health Heart Heart Rate Human In Situ In Vitro Individual Infarction Intervention Ion Channel Ions Kinetics Knowledge Lead Ligation Membrane Potentials Mesenchymal Stem Cells Modality Modeling Modification Morbidity - disease rate Muscle Cells Mutate Myocardial Infarction Outcome Pathway interactions Patients Pharmaceutical Preparations Prevention Prevention therapy Property Refractory Research Site Site-Directed Mutagenesis Specificity Speed Stress System Tail Techniques Testing Text Tissues Ventricular Ventricular Tachycardia Viral Viral Vector base density design gene therapy improved in vivo innovation mathematical model mortality mutant novel novel strategies overexpression premature prevent research study statistics sudden cardiac death

项目摘要

DESCRIPTION (provided by applicant): The overall objective of our proposed research is to use our knowledge of the pathophysiology of reentry and of myocardial infarct-associated ventricular tachycardia to hypothesize innovative, mechanism-based approaches to therapy Our general hypothesis is that gene therapy using adult human mesenchymal stem cells (hMSCs) as platforms and/or using viral vectors can deliver overexpressed ion channel gene constructs to prevent/suppress this arrhythmia. Our proposed 5-year plan incorporates: (1) identification and testing the effect of overexpression of specific gene constructs in viral vectors and in hMSC platforms to modify specific ion channel expression in cell lines; (2) using mathematical modeling, cell systems, and animal models that previously have been validated by us and others to test the mechanism of action, efficacy and proarrhythmic potential of each gene and cell therapy approach we design. We specifically hypothesize that gene and cell therapies can be antiarrhythmic by speeding conduction and/or prolonging refractoriness (but not repolarization) and study these possibilities in the canine heart in situ. Our first two Aims (stated as hypotheses) employ novel approaches to speed conduction. 1: A non-cardiac Na channel that shifts inactivation to more depolarized potentials will enhance Na current density in normal myocytes firing at high rates and preserve Na current density in depolarized myocytes. This should increase action potential (AP) upstroke velocity and conduction velocity, such that antegrade activation is normalized to prevent reentrant arrhythmias and/or the "head" of the activating wave catches the "tail" to terminate reentrant arrhythmias. 2: Increasing diastolic K conductance should restore depolarized membrane potentials towards normal and enhance excitability for normal myocytes at high stimulation frequencies. The third strategy is to prolong the effective refractory period (ERP) with regard to AP duration (APD). 3: Here, we hypothesize that overexpression of a mutant hERG with slowed deactivation kinetics should improve rate responsiveness and prolong ERP compared to APD. This should speed conduction at high heart rates while blocking propagation of premature depolarizations, reducing the likelihood of reentry. The significance of our proposed research is seen in the identification of novel ion channel constructs, testing them via in silico modeling and then in cell experiments to understand and fine-tune mechanism of action; using innovative means to administer them in cell systems and finally in intact animals to treat a reentrant rhythm - ventricular tachycardia - that is a major cause of morbidity and mortality in the US today. The selectivity and specificity of these approaches far exceed those of drugs and of ablation and open promising new vistas for arrhythmia treatment and prevention. PUBLIC HEALTH RELEVANCE: Cardiac arrhythmias remain a major disabler and killer of US citizens and current drug and device therapies are inconsistently effective and often create further problems. We propose to use the techniques of gene and cell therapy to deliver novel genes to the heart that will target sites of arrhythmia generation with high selectivity and efficacy and offer a safer modality of treatment

描述（由申请人提供）：我们提出的研究的总体目标是利用我们对折返和心肌梗塞相关室性心动过速的病理生理学知识来假设创新的、基于机制的治疗方法我们的一般假设是基因治疗使用成人间充质干细胞（hMSC）作为平台和/或使用病毒载体可以传递过度表达的离子通道基因构建体以预防/抑制这种心律失常。我们提出的五年计划包括：(1) 鉴定和测试病毒载体和 hMSC 平台中特定基因构建体的过表达对细胞系中特定离子通道表达的影响； (2) 使用我们和其他人之前验证过的数学模型、细胞系统和动物模型来测试我们设计的每种基因和细胞治疗方法的作用机制、功效和致心律失常潜力。我们特别假设基因和细胞疗法可以通过加速传导和/或延长不应期（但不是复极化）来抗心律失常，并在犬心脏中原位研究这些可能性。我们的前两个目标（作为假设陈述）采用新颖的方法来加速传导。图 1：将失活转移至更多去极化电位的非心脏 Na 通道将增强正常心肌细胞中高速率放电的 Na 电流密度，并保持去极化心肌细胞中的 Na 电流密度。这应该增加动作电位（AP）上冲速度和传导速度，使得顺行激活正常化以防止折返性心律失常和/或激活波的“头部”抓住“尾部”以终止折返性心律失常。 2：增加舒张期 K 电导应将去极化膜电位恢复至正常，并增强正常肌细胞在高刺激频率下的兴奋性。第三个策略是延长与 AP 持续时间 (APD) 相关的有效不应期 (ERP)。 3：在这里，我们假设与 APD 相比，具有减慢失活动力学的突变 hERG 的过度表达应该提高速率反应性并延长 ERP。这应该会加速高心率下的传导，同时阻止过早去极化的传播，从而降低再入的可能性。我们提出的研究的意义在于识别新型离子通道结构，通过计算机建模测试它们，然后在细胞实验中了解和微调作用机制；使用创新方法在细胞系统中施用它们，最后在完整的动物中施用它们来治疗折返性心律 - 室性心动过速 - 这是当今美国发病和死亡的主要原因。这些方法的选择性和特异性远远超过药物和消融，为心律失常的治疗和预防开辟了充满希望的新前景。公共卫生相关性：心律失常仍然是美国公民的主要致残因素和杀手，目前的药物和设备治疗效果不一致，常常会产生进一步的问题。我们建议使用基因和细胞治疗技术将新基因输送到心脏，以高选择性和有效性靶向心律失常发生部位，并提供更安全的治疗方式