A Molecular Study of Cardiac Repolarization

心脏复极的分子研究

• 批准号: 7169878
• 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
• 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/7169878
• 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

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）： 自从最早描述心电图以来，每次去极化之间的静止期就吸引了科学家。 现在已知心动周期的这个阶段是一系列高度协调的事件，恢复静息膜电位。 复极化是一个复杂的现象，依赖于单个通道、受体、细胞骨架和膜的功能，所有这些都在多细胞结构中。 在过去的十年中，复极的扰动直接涉及致命的心律失常。 考虑到这种对复极畸变的敏感性，有强大的机制来保护这一过程也就不足为奇了。 该领域的核心假设之一是，心脏具有复极储备，使其能够耐受复极的微小扰动，但可能会被严重或累积的损伤所压倒。 鉴于这一过程的复杂性，一个完整的动物模型有机体适合快速遗传操作和分析将需要更好地了解复极。 我们的初步数据表明，复极的干扰表现为心动过缓的斑马鱼，这种生物体将提供一个很好的模型，心脏复极的分析。 本研究拟从三个方面对斑马鱼心脏复极进行系统的研究：1）建立斑马鱼对lKr阻断药物的心动过缓反应机制; 2）鉴定人类长QT综合征基因的斑马鱼直系同源基因并评估其在斑马鱼心脏复极中的作用; 3）通过调节斑马鱼复极化的分子决定因子，系统地检验复极化储备的概念。 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研究金培训。 Milan博士于2003年7月被任命为MGH心脏科的工作人员，该部门为他的工作投入了大量资源。 他已经召集了一个由三个赞助商组成的小组，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指导他。 米兰博士的顾问小组包括心脏复极化，心肌细胞信号转导和药物诱导的心律失常领域的领导者。 米兰博士将通过一个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Milan博士的科学、专业和个人发展，最终使他成为基础心脏电生理学领域的独立研究者。