Perturbed Sodium and Calcium Fluxes in Atrial Fibrillation

心房颤动中钠和钙通量的扰动

基本信息

批准号：
9276787
负责人：
Eleonora Grandi
金额：
$ 39.39万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276787
关键词：
Action Potentials Acute Address Adrenergic Agents Affect Age Anti-Arrhythmia Agents Arrhythmia Atrial Fibrillation Behavior Biochemical Biological Models Biophysics Calcium/calmodulin-dependent protein kinase Calmodulin Cardiac Cardiac Electrophysiologic Techniques Cell physiology Cells Chronic Clinic Complex Computer Simulation Computer software Cyclic AMP-Dependent Protein Kinases Data Databases Dependence Development Disease Disease Progression Drug Design Drug Interactions Drug Targeting Electrophysiology (science)Failure Formulation Functional disorder Gated Ion Channel General Population Heart Atrium Heart Diseases Heart failure Homeostasis Human Hyperactive behavior Image Impairment Investigation Ion Channel Ion Channel Gating Kinetics Lead Link Maintenance Mathematics Measurement Mediating Mediator of activation protein Membrane Potentials Modeling Molecular Molecular Conformation Muscle Cells Nodal Pathology Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Population Potassium Channel Predisposition Progressive Disease Publishing Quality of life Radiofrequency Interstitial Ablation Recurrence Refractory Regulation Research Research Infrastructure Risk Safety Sampling Signal Pathway Signal Transduction Sinus Site Sodium Source Specificity Stroke Study models System Systolic heart failure Testing Therapeutic Tissues Treatment outcome Ventricular Ventricular Dysfunction base burden of illness channel blockers computer studies drug efficacy effective therapy experimental study hemodynamics human data improved indium arsenide insight mathematical analysis mathematical model models and simulation mortality nerve supply novel novel therapeutics patch clamp prevent ranolazine release of sequestered calcium ion into cytoplasm response sobriety synergism tool validation studies virtual voltage

项目摘要

PROJECT SUMMARY: Atrial fibrillation (AF) is the most common cardiac arrhythmia (affecting ~1-2% of the general population), resulting in markedly reduced quality of life, and increased mortality, due to a combination of altered hemodynamics, progressive atrial and ventricular dysfunction, and embolic stroke. Patients with sporadic AF episodes (paroxysmal AF) are more amenable to rhythm control treatment, but limitation in current pharmacotherapy causes paroxysmal AF to progress to persistent and chronic AF, characterized by extensive remodeling that facilitates AF maintenance (“AF begets AF”). The development of urgently needed new strategies for AF treatment hinge upon improved understanding of how abnormalities in cellular function (remodeled ion channels, Ca and Na handling, and cellular signaling), together with neurohormonal regulation trigger and sustain arrhythmia in the atria. Understanding the interactions of these complex biochemical and biophysical functions requires quantitative systems models that also integrate over multiple physical scales. To address this complex problem, we aim at developing an integrative and quantitative modeling and simulation framework, incorporating data from experimental sources, to investigate emerging questions in AF. We propose a closely integrated combination of experimental and computational studies that takes advantage of interdisciplinary synergy between Drs. Grandi & Chiamvimonvat at UC Davis and Dr. Dobrev at Universitätsklinikum Essen. The project will develop and validate a suite of modeling tools used to investigate mechanistically: (1) how derangements in Ca and Na homeostasis, CaMKII hyperactivation, and β-adrenergic challenge contribute to cellular afterdepolarizations and triggered activity in early and chronic human AF; (3) the efficacy and safety (AF-selectivity) of antiarrhythmic drugs targeting cardiac Na channels and atrial-specific small conductance Ca-activated K channels, to facilitate rational drug design. We contend that understanding how CaMKII signaling synergizes with ionic and Ca and Na handling remodeling, as well as neurohormonal regulation, may shed mechanistic insight into AF management. Each aim includes formulation and sensitivity analysis of new models (Dr. Sobie is a consultant), validation studies with human samples, and testing of specific hypotheses. Models and data will be distributed freely and widely via software and database infrastructure supported by Dr. Grandi's lab and scientific networking sites.

项目摘要：心房颤动 (AF) 是最常见的心律失常（影响约 1-2% 的心律失常）一般人群），导致生活质量显着下降，死亡率增加，血流动力学改变、进行性心房和心室功能障碍以及栓塞性中风患者。散发性房颤发作（阵发性房颤）更适合节律控制治疗，但目前的局限性药物治疗会导致阵发性 AF 发展为持续性和慢性 AF，其特点是广泛促进 AF 维护的重塑（“AF 产生 AF”）迫切需要的新产品的开发。房颤治疗策略取决于对细胞功能异常如何发生的更好理解（重塑离子通道、Ca 和 Na 处理以及细胞信号传导）以及神经激素调节了解这些复杂的生化和维持心律失常的相互作用。生物物理功能需要定量系统模型，该模型也可以在多个物理尺度上集成。为了解决这个复杂的问题，我们的目标是开发一种集成的定量建模和模拟方法框架，结合来自实验来源的数据，来研究 AF 中出现的问题。实验和计算研究的紧密结合提出，利用加州大学戴维斯分校的 Grandi 和 Chiamvimonvat 博士与 Dobrev 博士之间的跨学科协同作用 Universitätsklinikum Essen。该项目将开发和验证一套用于调查的建模工具。机制上：(1) Ca 和 Na 稳态紊乱、CaMKII 过度激活和 β-肾上腺素能如何紊乱在早期和慢性人类 AF 中促进细胞后除极和触发活动的挑战 (3) 针对心脏通道和心房特异性的抗心律失常药物的有效性和安全性（AF 选择性）小电导Ca激活K通道，有利于我们合理的药物设计理解。 CaMKII 信号传导如何与离子、Ca 和 Na 处理重塑以及神经激素协同作用监管，可能会揭示对 AF 管理的机制洞察。每个目标都包括制定和敏感性。新模型分析（Sobie 博士是顾问）、人体样本验证研究以及测试具体假设和数据将通过软件和数据库自由且广泛地分发。格兰迪博士的实验室和科学网站支持的基础设施。