Focal Modification of Electrical Conduction in the Heart

心脏电传导的局部改变

• 批准号: 6828272
• 负责人: J Kevin Donahue
• 金额: $ 40.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6828272
• 关键词: Adenoviridae; G protein; arrhythmia; atrial fibrillation; atrioventricular node; biotechnology; electrocardiography; electrophysiology; gene delivery system; gene expression; gene therapy; genetic manipulation; heart; heart conduction system; heart rate; laboratory rabbit; myocardium; potassium channel; protein localization; swine; technology /technique development; tissue /cell preparation; transfection /expression vector; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Conventional approaches for the treatment of cardiac arrhythmias are limited to pharmacotherapy, ablation or implantable devices. Each of these strategies is effective in certain situations, but each is also associated with a number of untoward effects. With the limitations of currently available therapies, there is a need for new approaches to treat common cardiac arrhythmias. The central hypothesis of this proposal is that genetic manipulation of the cardiac substrate in a controlled, localized manner can effectively treat cardiac arrhythmias. As an initial attempt to investigate this theory, we will focus on the atrioventricular node, an anatomically well-defined region where functional changes are easily observed. Realizing the limitations of prior in vivo gene transfer strategies, this proposal seeks to investigate the central hypothesis in a systematic fashion by defining the variables important for vector delivery, by limiting the area of investigation to a specific intracardiac region, and by using conventional cellular techniques to investigate the mechanisms responsible for the observed phenotypic changes. To that end, the overall goal of this proposal will be to suppress AV nodal conduction in a controllable manner, sufficient to reduce the heart rate during atrial fibrillation but not to produce complete AV block. The specific aims to be addressed include: 1) To evaluate the effect of manipulating basic physiological variables on the efficiency of in vivo gene delivery to the AV node. 2) To evaluate the effect on AV nodal conduction of gene transfer-induced alterations in cellular levels of G proteins and potassium channels, and 3) To characterize the cellular mechanisms responsible for suppression of AV nodal conduction in states of gene transfer-induced protein overexpression. Successful completion of these aims will provide proof of principle that gene therapy strategies are viable options for the future treatment of common cardiac arrhythmias.

描述（由申请人提供）：常规治疗方法 心律失常的治疗仅限于药物治疗、消融或植入 设备。这些策略中的每一种在某些情况下都是有效的，但是每种策略 还与许多不良影响有关。随着限制 目前可用的治疗方法，需要新的治疗方法 常见的心律失常。该提案的中心假设是 以受控、局部的方式对心脏基质进行基因操作 可有效治疗心律失常。作为初步调查尝试 根据这个理论，我们将重点关注房室结，在解剖学上 易于观察功能变化的明确区域。实现 鉴于先前体内基因转移策略的局限性，该提案旨在 通过定义 通过限制研究范围，对载体传递很重要的变量 到特定的心内区域，并通过使用传统的细胞 研究造成所观察到的现象的机制的技术 表型变化。为此，本提案的总体目标是 以可控方式抑制房室结传导，足以减少 心房颤动期间的心率但不产生完全的房室传导阻滞。这 要解决的具体目标包括： 1) 评估效果 操纵基本生理变量影响体内基因的效率 传送到 AV 节点。 2) 评估对房室结传导的影响 基因转移引起的 G 蛋白细胞水平的改变 钾通道，以及 3) 表征负责的细胞机制 用于在基因转移诱导状态下抑制房室结传导 蛋白质过度表达。成功完成这些目标将提供证明 原则上，基因治疗策略是未来可行的选择 治疗常见的心律失常。