Multi-Scale Modeling of Arrhythmias

心律失常的多尺度建模

• 批准号: 8133289
• 负责人: ZHILIN QU
• 金额: $ 30.94万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133289
• 关键词: Accounting; Address; Arrhythmia; Biological Response Modifier Therapy; Biology; Biomedical Engineering; Cessation of life; Complement; Complication; Computers; Goals; Heart; Heart Diseases; Heterogeneity; Implantable Defibrillators; Instruction; Mathematical Biology; Molecular; Organism; Pathogenesis; Process; Research; Substrate Interaction; System; Therapeutic; Tissues; United States; Ventricular Arrhythmia; Ventricular Fibrillation; experimental analysis; mortality; multi-scale modeling; novel; prevent; programs; sudden cardiac death; synergism; therapeutic development

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.

心室纤颤（VF）是心脏突然死亡（SCD）的NNOST常见原因，并说明了 仅在美国，每年每年30万人死亡。然而，尽管有50年的分子和细胞 研究，尚无生物疗法与植入式心脏verterdefbrilltator相当的疗效。 该提议的计划项目的目的是开发理性的新颖疗法以防止 通过更好地理解机械水平VF的发病机理的SCD。提案 继续我们的努力，始于我们在心脏突然死亡（1995-2004）中的得分，一直持续 在当前的计划项目（2005-2010）中，通过整合信息来解决这一目标 使用系统方法结合实验和 数学生物学。沿着这些线路继续，该程序项目将重点放在触发物质上 互动，与中心主题有关的与早期（eads）和延迟（爸爸）后置际相关的互动， 经典地认为是心律不齐的触发器，同时增强了组织的脆弱性 基板创建导致VF和SCD的环境。我们将分析动态之间的协同作用 在此过程中，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）在发展理论框架中，以实验分析在 项目2中的分子/细胞水平（心律不齐的细胞机制），项目3的组织水平 （心脏失败的心律失常和抗心律失常目标）以及项目4的治疗发展 （心律不齐治疗的分子方法），由3个核心促进（计算机和数学核心A，生物学 和生物工程核心B和行政核心c）。这些研究将共同​​提供关键 开发和推进这种重大并发症的新颖疗法所必需的基础工作 心脏病的死亡率。