Cardiac Fibrillation: Mechanisms and Therapy

心脏颤动：机制和治疗

基本信息

批准号：
6960159
负责人：
James N Weiss
金额：
$ 206.83万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-10 至 2010-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Ventricular fibrillation (VF) is the most common cause of sudden death, accounting for over 300,000 deaths annually in the US alone. The objective of this proposed Program Project is to develop a rational approach to the therapy of sudden cardiac death (SCO) through understanding the pathogenesis of VF at the mechanistic level. The proposal represents a continuation of our efforts, which began with our SCOR in Sudden Cardiac Death in 1995, to address this objective by combining mathematical biology with experimental biology to integrate information at the molecular, cellular, tissue and systems levels. The theme of this proposed Program Project is that dynamic wave instability (regulated by electrical restitution, intracellular Cai cycling, cardiac memory and diffusive currents) interacts synergistically with increased electrical and structural tissue heterogeneity in the diseased heart to increase the risk of VF and SCO, and that by developing molecular interventions designed to decrease dynamic wave instability, VF and SCO can be prevented. The four projects and three cores will address this theme using experimental approaches including patch clamping, optical mapping with fluorescent dyes, molecular biology, adenoviral gene transfer, and theoretical approaches including mathematical modeling, computer simulations and nonlinear dynamics. Studies ranging from isolated myocytes to intact normal and diseased ventricles, both in vivo and in silico, will be conducted interactively through this Program Project to evaluate comprehensively dynamic factors controlling wave stability as therapeutic targets for prevention of VF and SCO.

描述（由申请人提供）：心室颤动 (VF) 是猝死的最常见原因，仅在美国每年就有超过 300,000 人死亡。本拟议项目的目标是通过在机制层面了解心室颤动的发病机制，开发治疗心源性猝死 (SCO) 的合理方法。该提案代表了我们努力的延续，我们的努力始于我们的 SCOR 1995 年的心脏性猝死，通过将数学生物学与实验生物学相结合，整合分子、细胞、组织和系统水平的信息来实现这一目标。该拟议项目的主题是动态波不稳定性（由电恢复、细胞内蔡循环、心脏记忆和扩散电流调节）与患病心脏中电和结构组织异质性增加相互作用，从而增加 VF 和 SCO 的风险，通过开发旨在降低动态波不稳定性的分子干预措施，可以预防 VF 和 SCO。这四个项目和三个核心将利用膜片钳、荧光染料光学绘图、分子生物学、腺病毒基因转移等实验方法以及数学建模、计算机模拟和非线性动力学等理论方法来解决这一主题。从分离的肌细胞到完整的正常和患病心室的体内和计算机研究，将通过该项目以交互方式进行，以全面评估控制波稳定性的动态因素作为预防 VF 和 SCO 的治疗目标。