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：
8475498
负责人：
IRA S COHEN
金额：
$ 73.86万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8475498
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.

描述（由申请人提供）：我们拟议的研究的总体目标是利用我们对再入和心肌梗死相关的心室心动过速的病理生理学的了解，以假设基于创新的，基于机制的治疗方法成年人类间充质干细胞（HMSC）作为平台和/或使用病毒载体可以传递过表达的离子通道基因构建体，以防止/抑制这种心律不齐。我们提出的5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的影响，以修改细胞系中特定的离子通道表达；（2）使用以前已由我们和其他人验证的数学建模，细胞系统和动物模型来测试我们设计的每个基因和细胞疗法方法的作用机理，功效和心律失常的潜力。我们特别假设基因和细胞疗法可以通过超速传导和/或延长的耐火性（而不是复极化）来进行抗心律失常，并在原位研究这些可能性。我们的前两个目标（称为假设）采用新颖的方法来传导。 1：将失活转移到更多去极化电位的非心脏NA通道将以高速率发射的正常肌细胞发射的Na电流密度，并在去极化的肌细胞中保留Na电流密度。这应该增加动作电位（AP）上冲程速度和传导速度，从而使进步激活进行标准化，以防止重新进入心律不齐和/或激活波的“头”捕获“尾巴”以终止重新进入心律失常。 2：增加舒张期K电导应恢复正常的去极化膜电位，并在高刺激频率下增强对正常肌细胞的兴奋性。第三个策略是延长有关AP持续时间（APD）的有效耐火周期（ERP）。 3：在这里，我们假设与APD相比，失活动力学的突变体HERG的过表达应提高速率响应能力和延长的ERP。这应该以高心率的高速传导，同时阻止过度去极化的传播，从而降低重新进入的可能性。我们提出的研究的意义在鉴定新型离子通道构建体，通过计算机建模中对其进行测试，然后在细胞实验中对其进行测试，以理解和微调作用机理；使用创新的手段在细胞系统中进行管理，最后在完整的动物中治疗重入的节奏 - 心室心动过速 - 这是当今美国发病率和死亡率的主要原因。这些方法的选择性和特异性远远超过了药物和消融的选择性，并开放了有希望的心律失常治疗和预防的新远景。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior.

DOI：
10.1161/circulationaha.111.045146
发表时间：
2012-02-21
期刊：
Circulation
影响因子：
37.8
作者：
Mandel Y;Weissman A;Schick R;Barad L;Novak A;Meiry G;Goldberg S;Lorber A;Rosen MR;Itskovitz-Eldor J;Binah O
通讯作者：
Binah O

Stem cell-based biological pacemakers from proof of principle to therapy: a review.

DOI：
10.1016/j.jcyt.2014.02.014
发表时间：
2014-07
期刊：
CYTOTHERAPY
影响因子：
4.5
作者：
Chauveau, Samuel;Brink, Peter R.;Cohen, Ira S.
通讯作者：
Cohen, Ira S.

From beat rate variability in induced pluripotent stem cell-derived pacemaker cells to heart rate variability in human subjects.

DOI：
10.1016/j.hrthm.2014.05.037
发表时间：
2014-10
期刊：
HEART RHYTHM
影响因子：
5.5
作者：
Ben-Ari, Meital;Schick, Revital;Barad, Lili;Novak, Atara;Ben-Ari, Erez;Lorber, Avraham;Itskovitz-Eldor, Joseph;Rosen, Michael R.;Weissman, Amir;Binah, Ofer
通讯作者：
Binah, Ofer

The math of sisyphus: the conundrum of stem cell administration for myocardial infarction and myocardial failure.

西西弗斯的数学：干细胞治疗心肌梗塞和心肌衰竭的难题。