Arrhythmia Mechanisms of the Metabolic Sensor AMP Kinase

代谢传感器 AMP 激酶的心律失常机制

• 批准号: 6762840
• 负责人: VICKAS V PATEL
• 金额: $ 13.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6762840
• 关键词: adenylate kinase; arrhythmia; cardiac myocytes; electrocardiography; electrophysiology; enzyme activity; gene mutation; genetically modified animals; heart function; immunocytochemistry; in situ hybridization; laboratory mouse; molecular pathology; potassium channel; protein localization; protein structure function; sodium channel; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program to develop an academic career in molecular cardiac electrophysiology. The principal investigator has extensive training in clinical cardiac electrophysiology, basic electrophysiology, biophysics, and electrical engineering and will expand his scientific skills through a unique integration of interdisciplinary resources. This program will promote the command of molecular developmental biology, as applied to the development of cardiac arrhythmias and conduction disorders. Dr. Michael Parmacek will mentor the principal investigator's scientific development. He is a recognized leader in the field of molecular cardiac development and has trained numerous postdoctoral fellows and graduate students. To enhance the training, an advisory committee of highly regarded medical scientists will provide scientific and career guidance. The research will focus on mechanisms of arrhythmogenesis produced by mutations in the metabolic sensor AMP-activated protein kinase. Recent work has shown that mutations in AMP kinase produce familial Wolff-Parkinson-White syndrome in humans, and mice engineered with inhibitory mutations in their hearts die suddenly. The proposed experiments will use a combination of in vivo and in vitro electrophysiologic studies, biochemical and molecular techniques, and in situ localization analysis. We will study mice engineered with constitutively activating and inhibitory mutations in AMP kinase to elucidate the arrhythmogenic mechanisms of AMP kinase in the whole heart to the molecular level. The specific aims include: 1) determining the effect of mutations in AMP kinase upon cardiac arrhythmia inducibility, 2) determining if mutations in AMP kinase alter ion channel function, 3) determining if ion channel distribution is affected by mutations in AMP kinase that contribute to arrhythmogenesis. This will be the first functional analysis of how AMP kinase produces electrophysiologic disorders and may provide insight into novel mechanisms of arrhythmogenesis. The Cardiovascular Division of the University of Pennsylvania provides an ideal setting for training physician-scientists by incorporating expertise from diverse resources into customized training programs. Such an environment maximizes the potential for the principal investigator to establish scientific expertise from which to launch an independent academic career.

描述（由申请人提供）： 该提案描述了一项为期5年的培训计划，以发展分子心脏生理学的学术生涯。 首席研究员在临床心脏电生理学，基本电生理学，生物物理学和电气工程方面进行了广泛的培训，并将通过独特的跨学科资源整合来扩大他的科学技能。 该程序将促进分子发育生物学的指挥，以应用于心律不齐和传导障碍的发展。 迈克尔·帕尔马塞克（Michael Parmacek）博士将指导首席研究员的科学发展。 他是分子心脏发展领域的公认领导者，并培训了许多博士后研究员和研究生。 为了增强培训，由备受推崇的医学科学家组成的咨询委员会将提供科学和职业指导。 该研究将重点关注代谢传感器AMP激活蛋白激酶突变产生的心律失常发生的机制。 最近的工作表明，AMP激酶的突变会在人类中产生家族性的Wolff-Parkinson-White综合征，而在心脏中抑制性突变的小鼠突然死亡。 提出的实验将结合体内和体外电生理学研究，生化和分子技术以及原位定位分析。 我们将研究通过AMP激酶中组成型激活和抑制性突变设计的小鼠，以阐明整个心脏中AMP激酶的心律失常机制至分子水平。 具体目的包括：1）确定AMP激酶中突变对心律不齐诱导性的影响，2）确定AMP激酶改变离子通道函数中的突变是否是 3）确定离子通道分布是否受到心律失常发生的AMP激酶突变的影响。 这将是对AMP激酶如何产生电生理疾病的第一个功能分析，并可能提供对心律失常发生机制的新型机制。 宾夕法尼亚大学的心血管部门通过将各种资源的专业知识纳入定制的培训计划中，为培训医师科学家提供了理想的环境。 这样的环境最大程度地提高了主要研究人员建立科学专业知识的潜力，从而从中开展了独立的学术职业。