A Molecular Study of Cardiac Repolarization

心脏复极的分子研究

基本信息

批准号：
7339296
负责人：
David J Milan
金额：
$ 13.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7339296
关键词：
Action Potentials Animal Model Ankyrins Arrhythmia Binding Biological Assay Biology Bradycardia Cardiac Cardiac Myocytes Cardiology Cardiovascular system Cell physiology Cells Chemistry Classification Commit Complement Complex Cytoskeleton Data Depth Development Dominant-Negative Mutation Drug usage Dyes Electrocardiogram Electrophysiology (science)Embryo Ethers Ethyl Ether Event Fellowship Fishes Gene Expression Generations Genes Genetic Genetic Models Genomics Goals Heart Heart Diseases Heart Rate Heterogeneity Homologous Gene Human Individual Journals Knowledge Long QT Syndrome Maps Measurement Measures Membrane Membrane Potentials Mink Modeling Molecular Molecular Biology Mutation Optics Organism Orthologous Gene Pattern Pharmaceutical Preparations Phase Physiological Physiology Play Process Protein Overexpression Regulation Research Personnel Resources Rest Resting Phase Role Scientist Series Signal Transduction Staging Standards of Weights and Measures Structure System Techniques Testing Training Transgenic Organisms Work Zebrafish concept design fascinate genetic manipulation high throughput analysis human disease novel novel therapeutics prevent programs receptor research study response stem voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Since the earliest descriptions of the electrocardiogram, the period of quiescence between each depolarization, has fascinated scientists. This phase of the cardiac cycle is now known to be a highly orchestrated series of events that restore the resting membrane potential. Repolarization is a complex phenomenon, dependent on the functions of individual channels, receptors, cytoskeleton and the membrane, all within a multicellular structure. In the last decade, perturbations of repolarization have been directly implicated in fatal cardiac arrhythmias. Given this sensitivity to aberrations of repolarization, it is not surprising that there are robust mechanisms defending this process. One of the central hypotheses in the field is that the heart has a repolarization reserve that allows it to tolerate small perturbatations of repolarization, but which can be overwhelmed by severe or cumulative insults. Given the complexity of this process, an integrated whole animal model organism amenable to rapid genetic manipulation and analysis will be required for a better understanding of repolarization. Our preliminary data suggest that disturbances of repolarization are manifest as bradycardia in the zebrafish, and that this organism will provide a good model for the analysis of cardiac repolarization. This proposal takes a systematic approach to the study of cardiac repolarization in the zebrafish in three specific aims: 1) establish the mechanism of bradycardia in response to lKr blocking drugs in the zebrafish; 2) characterize the zebrafish orthologs of the human long QT syndrome genes and assess their role in zebrafish cardiac repolarization; 3) systematically test the concept of repolarization reserve by modulating the molecular determinants of repolarization in the zebrafish. The candidate has a background in chemistry and molecular biology and has recently completed cardiology and electrophysiology fellowship training. Dr. Milan was appointed to the staff of the Cardiology Division at MGH in July 2003, and the Division has committed numerous resources to his work. He has assembled a group of three sponsors who will guide him in both zebrafish biology and genetics and cardiovascular cellular physiology. Dr. Milan's panel of advisors includes leaders in the fields of cardiac repolarization, cardiomyocyte signal transduction and drug-induced cardiac arrhythmias. Dr. Milan will complement the experimental work described in this proposal with a comprehensive educational program including lab meetings, journal clubs, seminars, scientific meetings, and formal coursework. This plan is carefully designed to result in Dr. Milan's progressive scientific, professional and personal development, culminating in his emergence as an independent investigator in the field of basic cardiac electrophysiology.

描述（由申请人提供）：自从最早的心电图描述以来，每次去极化之间的静止期一直让科学家们着迷。现在已知心动周期的这一阶段是一系列高度精心安排的事件，可恢复静息膜电位。复极化是一种复杂的现象，取决于多细胞结构内各个通道、受体、细胞骨架和膜的功能。在过去的十年中，复极扰动与致命的心律失常直接相关。考虑到对复极化像差的敏感性，有强大的机制来保护这一过程也就不足为奇了。该领域的中心假设之一是，心脏具有复极储备，使其能够承受复极的小扰动，但可能会被严重或累积的损伤所淹没。考虑到这一过程的复杂性，为了更好地理解复极化，需要一个能够进行快速遗传操作和分析的完整的完整动物模型生物体。我们的初步数据表明，斑马鱼的复极紊乱表现为心动过缓，这种生物体将为分析心脏复极提供良好的模型。该提案采用系统的方法研究斑马鱼心脏复极的三个具体目标：1）建立斑马鱼对 lKr 阻断药物反应的心动过缓机制； 2）表征人类长QT综合征基因的斑马鱼直向同源物并评估它们在斑马鱼心脏复极中的作用； 3）通过调节斑马鱼复极的分子决定因素来系统地测试复极储备的概念。该候选人具有化学和分子生物学背景，最近完成了心脏病学和电生理学进修培训。 Milan 博士于 2003 年 7 月被任命为 MGH 心脏病科的工作人员，该科为他的工作投入了大量资源。他组建了一个由三名赞助商组成的小组，他们将在斑马鱼生物学和遗传学以及心血管细胞生理学方面为他提供指导。 Milan 博士的顾问小组包括心脏复极、心肌细胞信号转导和药物引起的心律失常领域的领导者。米兰博士将通过全面的教育计划来补充本提案中描述的实验工作，包括实验室会议、期刊俱乐部、研讨会、科学会议和正式课程。该计划经过精心设计，旨在促进米兰博士在科学、专业和个人方面的进步，最终使他成为基础心脏电生理学领域的独立研究者。