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）是最常见的心律不齐（影响约1-2％一般人口），由于组合而导致的生活质量显着降低和死亡率增加血液动力学改变，进行性心房和心室功能障碍以及栓塞性中风的改变。患者零星的AF发作（阵发性AF）更适合节奏控制治疗，但目前的限制药物疗法导致阵发性AF进展到持久性和慢性AF，其特征是广泛重塑可有助于AF维护（“ AF BEGES AF”）。迫切需要新的发展 AF治疗的策略在改善了对细胞功能异常的理解之后的铰链策略（重塑离子通道，CA和NA处理以及细胞信号传导）以及神经激素调节触发和维持心房心律不齐。了解这些复杂的生化和生物物理功能需要定量系统模型，这些模型也可以在多个物理尺度上集成。到解决这个复杂的问题，我们旨在开发一个集成和定量的建模和仿真框架，编码实验来源的数据，以研究AF中的新兴问题。我们提案的实验和计算研究紧密整合的组合，利用 Drs之间的跨学科协同作用。加州大学戴维斯分校的Grandi＆Chiamvimonvat和Dobrev博士在 UniversitätsklinikumEssen。该项目将开发并验证一套用于调查的建模工具机械学：（1）CA和NA稳态，CAMKII过度激活和β-肾上腺素能的演变如何挑战有助于细胞过度过度术，并触发早期和慢性人类AF的活性；（3）靶向心脏NA通道和心房特异性药物的抗心律失常药物的效率和安全性（AF-sectivity）小电导CA激活的K通道，以促进合理的药物设计。我们认为理解 CAMKII信号如何与离子和CA和NA处理重塑以及神经激素协同作用法规，可能会使机械洞察力对AF管理。每个目标都包括公式和灵敏度分析新模型（Sobie博士是顾问），对人类样本的验证研究以及测试特定的假设。模型和数据将通过软件和数据库自由和广泛分发 Grandi博士实验室和科学网络网站支持的基础设施。