Cardiac Fibrillation: Mechanisms and Therapy

心脏颤动：机制和治疗

• 批准号: 8079169
• 负责人: James N Weiss
• 金额: $ 210.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079169
• 关键词: Cardiac; Fibrillation; Mechanisms; Therapy

DESCRIPTION (provided by applicant): Ventricular fibrillation (VF) is the most common cause of sudden cardiac death (SCD), and accounts for over 300,000 deaths per year in the United States alone. However, despite 50 years of molecular and cellular research, no biological therapy has yet emerged with comparable efficacy to the implantable cardioverter- defibrillator. The objective of this proposed Program Project is to develop rational novel therapies to prevent SCD through a better understanding of the pathogenesis of VF at the mechanistic level. The proposal continues our efforts, which began with our SCOR in Sudden Cardiac Death (1995-2004) and has continued in the current Program Project (2005-2010), to address this objective by integrating information at the molecular, cellular, tissue and organism levels using a systems approach combining experimental and mathematical biology. Continuing along these lines, this Program Project will focus on trigger-substrate interactions, with the central theme related to how early (EADs) and delayed (DADs) afterdepolarizations, classically considered as arrhythmia triggers, simultaneously enhance the vulnerability of the tissue substrate to create the milieu leading to VF and SCD. We will analyze the synergism between dynamic factors and pre-existing tissue heterogeneities in this process. Project 1 (Multi-scale Modeling of Arrhythmias) will develop the theoretical framework, complemented by the experimental analysis at the molecular/cellular level in Project 2 (Cellular Mechanisms of Arrhythmias), the tissue level in Project 3 (Arrhythmias and Antiarrhythmic Targets in Failing Hearts), and therapeutic development in Project 4 (Molecular Approaches to Arrhythmia Therapy), facilitated by 3 cores (Computer and Math Core A, Biology and Bioengineering Core B, and Administrative Core C). Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease.

描述（由申请人提供）： 心室颤动 (VF) 是心源性猝死 (SCD) 的最常见原因，仅在美国每年就有超过 300,000 人死亡。然而，尽管分子和细胞研究进行了 50 年，但尚未出现与植入式心律转复除颤器具有可比性的生物疗法。本拟议项目的目标是通过更好地了解 VF 的发病机制，开发合理的新疗法来预防 SCD。该提案延续了我们的努力，从我们的心源性猝死 SCOR（1995-2004 年）开始，并在当前的计划项目（2005-2010 年）中继续努力，通过整合分子、细胞、组织和有机体的信息来实现这一目标。使用结合实验和数学生物学的系统方法来达到水平。继续沿着这些思路，该计划项目将重点关注触发因素与基质的相互作用，中心主题涉及早期（EAD）和延迟（DAD）后除极（传统上被认为是心律失常触发因素）如何同时增强组织基质的脆弱性，以产生导致 VF 和 SCD 的环境。我们将分析这个过程中动态因素和预先存在的组织异质性之间的协同作用。项目1（心律失常的多尺度建模）将开发理论框架，并辅以项目2（心律失常的细胞机制）中分子/细胞水平的实验分析、项目3（心律失常和失败的抗心律失常目标）的组织水平心脏），以及项目 4（心律失常治疗的分子方法）中的治疗开发，由 3 推动核心（计算机和数学核心 A、生物和生物工程核心 B 以及管理核心 C）。总之，这些研究将为开发和推进针对心脏病这一主要并发症和死亡原因的新疗法提供必要的关键基础。