Genetic and physiologic dissection of the vertebrate cardiac conduction system.
Genetic and physiologic dissection of the vertebrate cardiac conduction system.
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脊椎动物心脏传导系统的遗传和生理解剖。
DOI：
10.1371/journal.pbio.0060109
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发表时间：
2008-05-13
期刊：
影响因子：
9.8
通讯作者：
Stainier DY
中科院分区：
文献类型：
--
作者：
Chi NC;Shaw RM;Jungblut B;Huisken J;Ferrer T;Arnaout R;Scott I;Beis D;Xiao T;Baier H;Jan LY;Tristani-Firouzi M;Stainier DY
脊椎动物的心脏依赖于形成心脏传导系统（CCS）的高度特化的心肌细胞，以协调心室收缩并有效地单向驱动整个生物体的血液。这种特殊的线路系统的缺陷会导致晕厥和心脏性猝死。因此，更好地了解心脏传导的发展可能有助于防止这些破坏性的临床结果。利用心脏特异性荧光钙指示剂斑马鱼转基因系，Tg（cmlc 2：gCaMP）s878，允许在体内光学映射分析在完整的动物，我们确定和分析了四个不同的阶段，心脏传导发展，对应于细胞和解剖学的变化，发展中的心脏。此外，我们观察到，表观遗传因素，如血流动力学流量和收缩，调节这个专门的电系统的快速传导网络。为了鉴定CCS的新型调节剂，我们设计并进行了一种新的、基于生理学的正向遗传筛选，并首次鉴定了17种传导特异性突变。hobgoblins 634的定位克隆揭示了tcf 2，一种与年轻人成熟型糖尿病和家族性肾小球囊性肾病有关的同源框转录因子基因，也调节心房和心室之间的传导。Tg（cmlc 2：gCaMP）s878线/体内光学映射技术和心脏传导突变体的表征相结合，提供了一种新的多学科方法，以进一步了解脊椎动物CCS的分子决定因素。心脏异常的电活动，也称为心律失常，可能会破坏心脏收缩，导致意识丧失和猝死。每年，美国大约有45万人死于这种疾病。目前，对于心脏性猝死，唯一被证明有效的预防性治疗是自动植入式心律转复除颤器，这给患者带来了巨大的负担和成本。对心脏传导系统（协调心脏的节律性跳动）的更深入了解，可能会为这些患者带来新的更安全的治疗选择。利用斑马鱼这一了解人类疾病的高效模型系统，我们开发了一种心脏特异性荧光钙指示剂斑马鱼转基因系，以分析心脏传导系统的形成。使用这种荧光转基因株系，我们观察到四个不同的生理心脏传导阶段，对应于发育中的心脏的细胞和解剖变化。此外，我们还设计并进行了一种新的、基于生理学的正向遗传筛查，以识别在以前的筛查中可能无法发现的心脏传导突变体。总的来说，这些研究可能证明有利于开发旨在维持和/或改善整体心脏健康的治疗方案。通过表征脊椎动物心脏传导系统的遗传基础，一项新的研究揭示了心律失常的潜在机制，心律失常每年导致数十万人猝死。
Vertebrate hearts depend on highly specialized cardiomyocytes that form the cardiac conduction system (CCS) to coordinate chamber contraction and drive blood efficiently and unidirectionally throughout the organism. Defects in this specialized wiring system can lead to syncope and sudden cardiac death. Thus, a greater understanding of cardiac conduction development may help to prevent these devastating clinical outcomes. Utilizing a cardiac-specific fluorescent calcium indicator zebrafish transgenic line, Tg(cmlc2:gCaMP)s878, that allows for in vivo optical mapping analysis in intact animals, we identified and analyzed four distinct stages of cardiac conduction development that correspond to cellular and anatomical changes of the developing heart. Additionally, we observed that epigenetic factors, such as hemodynamic flow and contraction, regulate the fast conduction network of this specialized electrical system. To identify novel regulators of the CCS, we designed and performed a new, physiology-based, forward genetic screen and identified for the first time, to our knowledge, 17 conduction-specific mutations. Positional cloning of hobgoblins634 revealed that tcf2, a homeobox transcription factor gene involved in mature onset diabetes of the young and familial glomerulocystic kidney disease, also regulates conduction between the atrium and the ventricle. The combination of the Tg(cmlc2:gCaMP)s878 line/in vivo optical mapping technique and characterization of cardiac conduction mutants provides a novel multidisciplinary approach to further understand the molecular determinants of the vertebrate CCS. Aberrant electrical activity of the heart, otherwise known as cardiac arrhythmia, may disrupt heart contractions, leading to loss of consciousness and sudden death. Every year, approximately 450,000 individuals in the United States die suddenly from this event. Currently, the only proven preventive therapy for sudden cardiac death is the automatic implantable cardioverter defibrillator, which carries a significant burden and cost to the patient. Greater understanding of the cardiac conduction system, which coordinates rhythmic beating of the heart, may lead to novel and safer therapeutic options for these patients. Working with zebrafish, a productive model system for understanding human disease, we have developed a cardiac-specific fluorescent calcium indicator zebrafish transgenic line to analyze the formation of the cardiac conduction system. Using this fluorescent transgenic line, we have observed four distinct physiologic cardiac conduction stages that correspond to cellular and anatomic changes of the developing heart. Furthermore, we have designed and performed a new, physiology-based, forward genetic screen to identify cardiac conduction mutants that would have escaped discovery in previous screens. Overall, these studies may prove rewarding toward developing therapeutic options aimed at maintaining and/or improving overall cardiac health. By characterizing the genetic underpinnings of the vertebrate cardiac conduction system, a new study sheds light on the mechanisms underlying cardiac arrhythmias, which cause the sudden death of hundreds of thousands of people each year.
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影响因子：
10.8
作者：
Hoogaars, WMH;Tessari, A;Christoffels, VM
通讯作者：
Christoffels, VM
DOI：
10.1073/pnas.95.12.6815
发表时间：
1998-06-09
影响因子：
11.1
作者：
Gourdie, RG;Wei, Y;Mikawa, T
通讯作者：
Mikawa, T
DOI：
10.1073/pnas.0502679102
发表时间：
2005-12-06
影响因子：
11.1
作者：
Langenbacher, AD;Dong, Y;Chen, JN
通讯作者：
Chen, JN
影响因子：
56.9
作者：
Huisken, J;Swoger, J;Stelzer, EHK
通讯作者：
Stelzer, EHK
影响因子：
20.1
作者：
KANTER, HL;LAING, JG;SAFFITZ, JE
通讯作者：
SAFFITZ, JE