Multi-Scale Modeling of Arrhythmias

室颤(VF)是心源性猝死(SCD)的最常见原因，约占 仅在美国每年就有30万人死亡。然而，尽管50年来分子和细胞 研究表明，目前还没有出现可与植入型心律转复除颤器相媲美的生物疗法。 这个计划项目的目标是开发合理的新疗法来预防 通过从机制水平上更好地了解室性心动过速的发病机制。这项建议 继续我们的努力，这始于我们在心脏性猝死(1995-2004)中的SCOR，并一直在继续 在当前的方案项目(2005-2010)中，通过在 分子、细胞、组织和生物体水平使用系统方法结合实验和 数学生物学。继续沿着这些路线，本计划项目将专注于触发器衬底 相互作用，中心主题涉及多早(EADS)和延迟(DADS)后除极， 传统上被认为是心律失常的触发者，同时增强了组织的脆弱性 底物以创造导致室颤和SCD的环境。我们将分析动态之间的协同效应 这一过程中的因素和预先存在的组织异质性。项目1(多尺度建模 心律失常)将发展理论框架，并辅之以 项目2(心律失常的细胞机制)中的分子/细胞水平，项目3中的组织水平 (心脏衰竭中的心律失常和抗心律失常靶点)，以及项目4中的治疗进展 (心律失常治疗的分子方法)，由3个核心(计算机和数学核心A，生物学)推动 和生物工程核心B，以及管理核心C)。总之，这些研究将提供关键的 为开发和推进针对这一主要并发症和病因的新疗法所需的基础工作 心脏病死亡率。

Ventricular fibrillation (VF) is the nnost 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 cardioverterdefibrillator. 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 ofthe 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) wiil 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.