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Access Paths for Sodium-Channel Blocking Antiarrhythmics

钠通道阻断抗心律失常药物的进入途径

基本信息

批准号：
6932373
负责人：
PETER J LEE
金额：
$ 10.02万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-05 至 2006-04-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6932373
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

项目摘要

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5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性心律失常更好的药理学干预的见解。它还作为一个培训计划，为主要研究者作为一名医生科学家的学术生涯的发展。主要研究者在Harry A博士的指导下完成了心脏病学和博士后研究。Fozzard在芝加哥大学，并将继续领导一个基础心脏电生理学的独立项目。 Fozzard博士将继续指导主要研究者的发展，他是现代基础心脏电生理学的先驱之一，培养了许多研究员和学生，他们后来成为世界各地的杰出研究人员。由备受推崇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。研究项目的重点是抗心律失常药物通过结合和解除结合电压门控钠通道来调节使用依赖性阻滞的途径。该提案建立在Fozzard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）在局部缺血中常见的膜去极化对利多卡因和相关化合物的药物-通道相互作用的影响，2）鉴定其他药物途径以更好地表征药物-通道相互作用并获得对钠通道结构的进一步了解，3）检查对其他类别的抗心律失常药物的使用依赖性活性重要的药物途径，和4）扩展到初步发现，表明钠通道中的长QT突变改变了药物途径，从而改变了某些抗心律失常药物的使用依赖性。芝加哥大学是一所在医学和基础科学方面具有国际知名度的大学，为培养成功的学术生涯提供了严格的学术环境和广泛的资源。