Access Paths for Sodium-Channel Blocking Antiarrhythmics

钠通道阻断抗心律失常药物的进入途径

• 批准号: 6642181
• 负责人: PETER J LEE
• 金额: $ 13.12万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-05 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642181
• 关键词: Mammalia; antiarrhythmic agent; disopyramide; electrophysiology; heart electrical activity; ion channel blocker; lidocaine; long QT syndrome; membrane potentials; pharmacokinetics; protein binding; protein structure function; sodium channel; voltage gated channel

DESCRIPTION (provided by applicant): The proposal describes a 5-year plan to study the interaction between antiarrhythmic drugs and cardiac sodium channels with an ultimate goal of obtaining insights for a better pharmacologic intervention for deadly arrhythmia. It also serves as a training program for the development of an academic career for the principal investigator as a physician scientist. The principal investigator has completed cardiology and postdoctoral fellowships under the guidance of Dr. Harry A. Fozzard at the University of Chicago and will proceed to lead an independent program in basic cardiac electrophysiology. Dr. Fozzard, who will continue to mentor the principal investigator's development, is one of the pioneers in modern basic cardiac electorphysiology and has trained numerous fellows and students, who have since become prominent researchers throughout the world. The Advisory Committee of highly regarded basic and clinical scientists will provide both scientific and career guidance. Research program focuses on the paths through which antiarrhythmic drugs bind and unbind the voltage-gated sodium channel to modulate the use-dependent block. The proposal builds on the foundations of prior studies in Dr. Fozzard's and other laboratories and uses the framework developed by the principal investigator recently. The specific aims include; 1) the effects of membrane depolarization, often seen in ischemia, on the drug-channel interaction of lidocaine and related compounds, 2) identification of other drug-paths to better characterize the drug-channel interactions and gain further insights into the structure of sodium channel, 3) examine the drug-paths important for use-dependent activities of other classes of antiarrhythmic drugs, and 4) expand into the preliminary findings suggesting that a long-QT mutation in the sodium channel alters drug-paths and consequently use-dependent properties of certain antiarrythmic drugs. The University of Chicago, an institution of international prominence in medical and basic science provides a rigorous academic environment with extensive resources for fostering a successful academic career.

描述（由申请人提供）： 该提案描述了一项为期五年的计划，研究抗心律失常药物与心脏钠通道之间的相互作用，最终目标是获得对致命心律失常更好的药物干预的见解。 它还作为主要研究者作为医学科学家的学术职业发展的培训计划。 首席研究员在芝加哥大学 Harry A. Fozzard 博士的指导下完成了心脏病学和博士后研究，并将继续领导基础心脏电生理学的独立项目。 Fozzard 博士将继续指导首席研究员的发展，他是现代基础心脏电生理学的先驱之一，并培养了众多研究员和学生，他们后来成为世界各地的杰出研究人员。 由备受尊敬的基础和临床科学家组成的咨询委员会将提供科学和职业指导。 研究计划的重点是抗心律失常药物结合和解开电压门控钠通道以调节使用依赖性阻滞的路径。 该提案建立在福扎德博士和其他实验室先前研究的基础上，并使用了首席研究员最近开发的框架。 具体目标包括： 1) 缺血中常见的膜去极化对利多卡因及相关化合物的药物通道相互作用的影响，2) 识别其他药物路径，以更好地表征药物通道相互作用并进一步了解钠通道的结构，3) 检查对于其他类别抗心律失常药物的使用依赖性活性很重要的药物路径，4) 扩展到初步研究 研究结果表明，钠通道中的长 QT 突变会改变药物路径，从而改变某些抗心律失常药物的使用依赖性特性。 芝加哥大学是一所在医学和基础科学领域享有国际声誉的机构，提供严谨的学术环境和广泛的资源，以促进成功的学术生涯。