Investigation of arrhythmias in anthropomorphized murine cardiac myocytes.

拟人化小鼠心肌细胞心律失常的研究。

基本信息

批准号：
7690884
负责人：
Rebecca Clare Ahrens-Nicklas
金额：
$ 3.78万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2011-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690884
关键词：
Action Potentials Arrhythmia Behavior Calcium Calcium Channel Cardiac Cardiac Myocytes Cells Cessation of life Computational Biology Computational Technique Computer Simulation Couples Development Disease Electrophysiology (science)Elements Engineering Event Future Genetically Engineered Mouse Health Heart Arrest Heart Diseases Human Hybrids In Vitro Induced Mutation Inherited Investigation Ion Channel Kinetics Lead Long QT Syndrome Masks Mediating Membrane Membrane Potentials Methods Modeling Morphology Mus Muscle Cells Mutant Strains Mice Mutation National Heart, Lung, and Blood Institute Patch-Clamp Techniques Patients Phenotype Protocols documentation Running Simulate Staging Strategic Planning Study models Syncope Techniques Time Validation Wild Type Mouse disease-causing mutation experience heart cell heart rhythm human disease insight mathematical model mouse model mutant novel research study response sudden cardiac death theories voltage

项目摘要

DESCRIPTION (provided by applicant): This application presents and utilizes a new electrophysiology technique, the anthropomorphizing dynamic clamp (ADC) that increases the utility of genetically engineered mice in studies of inherited cardiac arrhythmias. Inherited channelopathies, such as the Long QT syndrome, are known causes of syncope, cardiac arrest, and sudden cardiac death. In the past decade, great progress has been made in identifying disease-causing mutations in patients. Several mouse models of these mutations have been produced; however, extrapolation of a mouse mutant phenotype to human disease is difficult because of the major differences between mouse and human cardiac electrophysiology dynamics. The technique proposed in this application uses a hybrid computational biology-electrophysiology method in order to examine isolated mouse myocytes in the context of a human action potential waveform. The ADC is a dynamic whole-cell patch clamp technique that couples an isolated murine cardiac myocyte to computational models. These models calculate a compensatory current which will allow a mouse myocyte to undergo a free-running human membrane potential. This will permit investigation of arrhythmogenic events, such as early after depolarizations, which are normally masked in the context of the short mouse action potential. Preliminary modeling studies have demonstrated that the ADC can be used to study the effects of a mutation introduced into a mouse myocyte on the human action potential. The ADC could be applied to a wide-range of mouse models of inherited channelopathies. Also, it is directly relevant to the NHLBI strategic plan, which specifically calls for the development of computational and experimental techniques that can help uncover the pathophysiologic mechanisms of cardiac diseases. Lay Summary: Disturbances in the normal rhythm of the heart (arrhythmias) can lead to serious health consequences, including death. Some people have inherited mutations which increase the likelihood of arrhythmias. Genetically engineered mice have been made in order to study these mutations; however, major differences exist between mouse and human heart rhythms. The new technique proposed in this application will convert the behavior of mouse heart cells to a more human-like state. Studies of mice using this technique should yield new insights into the mechanisms of heart rhythm diseases.

描述（由申请人提供）：本申请提出并利用了一种新的电生理学技术，即拟人化动态钳（ADC），该技术增加了基因工程小鼠在遗传性心律失常研究中的效用。遗传性通道病，例如长 QT 综合征，是晕厥、心脏骤停和心源性猝死的已知原因。在过去的十年中，在识别患者致病突变方面取得了巨大进展。已经建立了几种这些突变的小鼠模型；然而，由于小鼠和人类心脏电生理学动力学之间存在重大差异，因此很难将小鼠突变表型外推到人类疾病。本申请中提出的技术使用混合计算生物学-电生理学方法，以便在人类动作电位波形的背景下检查分离的小鼠肌细胞。 ADC 是一种动态全细胞膜片钳技术，可将分离的小鼠心肌细胞与计算模型耦合。这些模型计算补偿电流，使小鼠肌细胞能够承受自由运行的人体膜电位。这将允许研究心律失常事件，例如去极化后的早期，这些事件通常在短小鼠动作电位的背景下被掩盖。初步建模研究表明，ADC 可用于研究引入小鼠肌细胞的突变对人类动作电位的影响。 ADC 可应用于多种遗传性离子通道病小鼠模型。此外，它与 NHLBI 战略计划直接相关，该战略计划特别呼吁开发有助于揭示心脏病病理生理机制的计算和实验技术。外行总结：心脏正常节律紊乱（心律失常）可能会导致严重的健康后果，包括死亡。有些人患有遗传性突变，会增加心律失常的可能性。为了研究这些突变，人们培育出了基因工程小鼠。然而，小鼠和人类的心律之间存在重大差异。该应用中提出的新技术将把小鼠心脏细胞的行为转变为更类似于人类的状态。使用这种技术对小鼠进行的研究应该会对心律疾病的机制产生新的见解。