Multi-Scale Modeling of Arrhythmias

心律失常的多尺度建模

• 批准号: 8479412
• 负责人: ZHILIN QU
• 金额: $ 29.29万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8479412
• 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.

心室颤动 (VF) 是心源性猝死 (SCD) 的最常见原因，占超过 10% 仅在美国每年就有 30 万人死亡。然而，尽管分子和细胞研究已有 50 年的历史 研究表明，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开发合理的新疗法来预防 SCD 通过在机制层面更好地了解 VF 的发病机制。提案 我们继续努力，从心源性猝死 (1995-2004) 中的 SCOR 开始，并继续 在当前的计划项目（2005-2010）中，通过整合信息来实现这一目标 使用结合实验和技术的系统方法在分子、细胞、组织和生物体水平上 数学生物学。继续沿着这些思路，该计划项目将重点关注触发基底 相互作用，中心主题与后去极化的早期（EAD）和延迟（DAD）有关， 传统上被认为是心律失常的触发因素，同时增强组织的脆弱性 底物以创造导致 VF 和 SCD 的环境。我们将分析动态之间的协同作用 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）将开发理论框架，并辅以实验分析 项目2（心律失常的细胞机制）为分子/细胞水平，项目3为组织水平 （衰竭心脏的心律失常和抗心律失常目标）以及项目 4 中的治疗开发 （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 以及生物工程核心 B 和行政核心 C）。总之，这些研究将提供关键的 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 心脏病造成的死亡率。