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）： 由于心电图最早的描述，每个去极化之间的静止周期使科学家着迷。 现在众所周知，心脏周期的这一阶段是一系列精心策划的事件，可恢复静息膜电位。 重极化是一种复杂的现象，取决于单个通道，受体，细胞骨架和膜的功能，均在多细胞结构内。 在过去的十年中，复极的扰动已直接与致命心律不齐有关。 鉴于对复极畸变的敏感性，捍卫这一过程的机制有强大的机制并不奇怪。 该领域中的一个中心假设是，心脏具有复极储备，使其可以耐受复极化的小扰动，但可能会因严重或累积的侮辱而淹没。 鉴于此过程的复杂性，需要对快速遗传操作和分析进行整体动物模型生物，以更好地理解复极化。 我们的初步数据表明，复极的干扰在斑马鱼中表现为心动过缓，并且该生物将为心脏复极化分析提供良好的模型。 该提案采用系统的方法来研究斑马鱼中三个具体目的的心脏复极化：1）确定对斑马鱼中LKR阻断药物的响应的心动过缓机制； 2）表征人类长QT综合征基因的斑马鱼直系同源物，并评估其在斑马鱼心脏复极化中的作用； 3）通过调节斑马鱼中复极化的分子决定因素来系统地测试复极储备的概念。 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研究金培训。 米兰博士于2003年7月被任命为MGH心脏病学部的工作人员，该部门为他的工作提供了许多资源。 他组建了一组由三个赞助商组成的，他们将指导他的斑马鱼生物学和遗传学以及心血管细胞生理学。 米兰博士的顾问小组包括心脏复极化，心肌信号转导和药物引起的心律不齐的领域的领导者。 米兰博士将通过一项全面的教育计划来补充该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，以导致米兰博士的进步科学，专业和个人发展，最终是他在基本心脏电生理学领域的独立研究者的出现。