Molecular Approaches to Arrhythmia Therapy

心律失常治疗的分子方法

基本信息

批准号：
8376291
负责人：
Riccardo Olcese
金额：
$ 29.4万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-10 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8376291
关键词：
Adult Affect Amplifiers Anisotropy Arrhythmia Back Biological Biological Response Modifier Therapy Cardiac Cells Cicatrix Complement Computer Simulation Computers Coupled Coupling Dissection Down-Regulation Event Fibrosis Genetic Goals Heart Heart failure Heterogeneity Hybrids Hypokalemia Implantable Defibrillators Individual Intervention Kinetics Lead Life Long QT Syndrome Mediating Modeling Modification Molecular Muscle Cells Nifedipine Oryctolagus cuniculus Oxidative Stress Property Research Staging Study models Techniques Therapeutic Tissues United States Ventricular Ventricular Arrhythmia Ventricular Fibrillation Ventricular Premature Complexes Viral Vector Woman Work base channel blockers genetic manipulation improved mathematical model men novel overexpression patch clamp programs reconstitution research study sudden cardiac death therapeutic development virtual voltage

项目摘要

The goal of this Program Project is to develop novel antiarrhythmic approaches based on improved understanding of the arrhythmia mechanisms causing sudden cardiac death. Project 4 will combine biological experiments and mathematical modeling to study how the interaction between the L-type Ca curret (l{Ca,L}), the Ca{i} transient and other Ca-sensitive currents lead to early afterdepolarizations (EADs) in normal and failing ventricular myocytes (Aim 1). This analysis will then be used to guide development of therapeutic strategies to suppress EADs and EAD-mediated arrhythmias by modifying I{Ca,L} properties (Aim 2). We will utilize the dynamic patch clamp approach which permits virtual currents to be added and interact bidirectionally with the endogenous currents of a live myocyte. EADs will be induced with various interventions, and then suppressed by the Ca channel blocker nifedepine. In stages, the dynamic clamp will add back a virtual I{Ca,L} virtual Ca; transient, and other Ca-sensitive currents to determine the necessary interactions required to reconstitute EADs. Given the critical importance of the I{Ca,L} window current in EAD formation, we will use the dynamic clamp approach to explore how the kinetic and/or voltage dependent properties of I{Ca,L} can be modified to suppress "reconstituted" EADs in isolated myocytes. The normal I{Ca,L} in the dynamic clamp will be replaced with an appropriately modified virtual I{Ca,L} to identify which modifications eliminate EADs while preserving a normal Ca{i} transient (Aim 2a). Using this information, we will explore genetic modifications of I{Ca,L} in rabbit ventricular myocytes to identify interventions which suppress EADs without adversely affecting E-C coupling, using two strategies: i) genetic overexpression of ancillary Ca channel subunits to replace the corresponding native Ca channel subunits. ii) downregulation of native Ca channel subunits in the adult rabbit ventricular myocytes using appropriate viral vectors. These hybrid modeling/experimental studies promise to both advance our understanding of the mechanisms of EAD formation and identify novel antiarrhythmic strategies. Project 4 will be complemented by the modeling studies in Project 1, cellular level studies in P2, and tissue level studies in Project 3.

该计划项目的目的是基于改进的新型抗心律失常方法了解心律不齐机制导致心脏突然死亡。项目4将结合生物学实验和数学建模，以研究L型CA库雷的相互作用如何（l {ca，l}），ca {i}瞬态和其他CA敏感电流导致正常的早期倒流（EADS）和心室肌细胞失败（AIM 1）。然后，该分析将用于指导治疗的发展通过修改I {Ca，L}属性（AIM 2）来抑制EAD和EAD介导的心律不齐的策略。我们将利用动态斑块夹方法，该方法允许添加虚拟电流并进行交互与活肌细胞的内源性电流双向双向。 EADS将被各种干预措施，然后被CA通道阻滞剂Nifedepine抑制。在各个阶段，动态夹将添加一个虚拟I {Ca，L}虚拟CA;瞬态和其他CA敏感电流，以确定必要的重建EAD所需的互动。鉴于i {ca，l}窗口电流的至关重要性形成，我们将使用动态夹具方法来探索动力学和/或电压如何依赖可以修改I {Ca，l}的属性以抑制孤立的心肌细胞中的“重构” EAD。正常的i {ca，l}在动态夹具将用适当修改的虚拟I {Ca，L}替换，以识别哪些修改消除EADS，同时保留正常的Ca {i}瞬态（AIM 2A）。使用此信息，我们将探索兔心肌细胞中I {Ca，L}的遗传修饰，以识别抑制EAD的干预措施没有对E-C耦合的不利影响，使用两种策略：i）辅助CA的遗传过表达通道亚基替换相应的本机CA通道亚基。 ii）天然CA的下调使用适当的病毒载体的成年兔心室肌细胞中的通道亚基。这些混合动力建模/实验研究有望提高我们对EAD机制的理解形成并确定新型的抗心律失常策略。项目4将与建模相辅相成项目1的研究，P2中的细胞水平研究以及项目3的组织水平研究。