Genetic Regulation of Cardiac Patterning in Zebrafish

斑马鱼心脏模式的遗传调控

• 批准号: 8258456
• 负责人: DEBORAH YELON
• 金额: $ 38.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258456
• 关键词: Affect; Animal Model; Awareness; Biological; Blood Circulation; Cardiac; Cardiac Myocytes; Cell Count; Cells; Characteristics; Comprehension; Congenital Abnormality; Data; Development; Dimensions; Dissection; Embryo; Evaluation; Explosion; Fibroblast Growth Factor; Firearms; Genes; Genetic; Heart; Heart Atrium; Individual; Laboratory Research; Lateral Mesoderm; Light; Maintenance; Maps; Mediating; Modeling; Myocardium; Organ; Pathway interactions; Pattern; Physicians; Plastics; Play; Population; Production; Psychological reinforcement; Regenerative Medicine; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Stem cells; Surveys; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Tube; Ventricular; Work; Zebrafish; heart function; improved; innovation; migration; novel; progenitor; trait; transcription factor

DESCRIPTION (provided by applicant): Organ function relies upon the appropriate attributes of each of its individual operational components. For example, in the embryonic vertebrate heart, effective propulsion of circulation depends upon the distinct morphological, electrophysiological, and contractile traits of the atrial and ventricular chambers. Despite centuries of awareness of the key differences between atrial and ventricular cardiomyocytes, the fundamental mechanisms that allocate cells into chamber-specific lineages and direct chamber-specific differentiation remain largely mysterious. Our laboratory's research focuses on understanding the genetic pathways responsible for chamber fate assignment. By exploiting the utility of the zebrafish as a model organism, we have shown that the BMP and FGF signaling pathways differentially affect atrial and ventricular cell numbers, providing important clues to the mechanisms that initially establish the atrial and ventricular progenitor pools. Furthermore, our preliminary data indicate that initial chamber fate decisions can be plastic and that mechanisms exist to maintain chamber- specific characteristics in differentiated myocardium. Together, our studies suggest an intriguing model in which early patterning of the heart field, followed by later reinforcement of chamber identity, results in proper chamber fate assignment. Here, we propose to evaluate aspects of this model in detail. In Aim 1, we will delve deeper into the mechanisms responsible for the initial establishment of chamber progenitor pools. Specifically, we will use fate mapping, time-lapse tracking, mosaic analysis, and evaluation of candidate effector genes to determine how BMP signaling promotes the establishment of atrial progenitor cells. In Aim 2, we will investigate the mechanisms that maintain chamber identity. Employing transgenic reporters of chamber identity, time-lapse analysis, mosaic analysis, and dissection of chamber-specific regulatory sequences, we will test whether FGF signaling functions to insure maintenance of ventricular chamber identity by promoting expression of nkx genes. Finally, in Aim 3, we will pursue identification of new pathways that regulate chamber fate assignment, taking advantage of our discovery of 4 intriguing compounds that impact atrial or ventricular cardiomyocyte production. Together, our studies will illuminate new features of the network of pathways controlling chamber fate assignment. In the long term, this work has the potential to shed light on the causes of cardiac birth defects and to facilitate innovations in regenerative medicine. PUBLIC HEALTH RELEVANCE: Effective heart function depends upon the specific dimensions and functional characteristics of the atrial and ventricular cardiac chambers. However, the genetic pathways responsible for creating distinct atrial and ventricular tissues are not well understood. In the long term, a better comprehension of this topic will improve our understanding of the causes of common cardiac birth defects and will suggest strategies for directing chamber-specific differentiation of pluripotent cells for therapeutic purposes.

描述（由申请人提供）：器官功能依赖于其每个单个操作组件的适当属性。例如，在胚胎脊椎动物心脏中，有效的循环推进取决于心房和心室腔的独特的形态学，电生理和收缩性特征。尽管对心房和心室心肌细胞之间的关键差异的认识几个世纪，但将细胞分配到腔室特异性谱系和直接室特异性分化的基本机制仍然在很大程度上是神秘的。 我们的实验室研究重点是理解负责室内命运分配的遗传途径。通过利用斑马鱼作为模型生物的效用，我们表明，BMP和FGF信号通路会差异地影响房屋和心室细胞数，从而为最初建立心房和心室祖细胞池的机制提供了重要的线索。此外，我们的初步数据表明，初始室命运的决策可以是塑性的，并且存在维持分化心肌中腔室特异性的机制。我们的研究共同提出了一个有趣的模型，其中心脏场的早期模式，然后是后来加强腔室身份，从而导致适当的室命运分配。在这里，我们建议详细评估该模型的各个方面。在AIM 1中，我们将深入研究负责初始建立室祖细胞池的机制。具体而言，我们将使用命运映射，延时跟踪，镶嵌分析和评估候选效应子基因，以确定BMP信号如何促进心房祖细胞的建立。在AIM 2中，我们将研究维持房间身份的机制。采用腔室认同，延时分析，镶嵌分析和腔室特异性调节序列的解剖的转基因记者，我们将通过促进NKX基因的表达来测试FGF信号功能是否可以通过促进室内腔室身份维持。最后，在AIM 3中，我们将利用发现4种影响心房或心室心肌细胞产生的4种有趣化合物的新途径来识别调节室命运分配的新途径。 总之，我们的研究将阐明控制室命运分配的途径网络的新特征。从长远来看，这项工作有可能阐明心脏先天缺陷的原因并促进再生医学的创新。 公共卫生相关性：有效的心脏功能取决于心房和心室心房的特定维度和功能特征。然而，尚不清楚导致创建不同心房和心室组织的遗传途径。从长远来看，对该主题的更好理解将提高我们对常见心脏出生缺陷的原因的理解，并将提出指导多能细胞的特定于室特异性分化的策略，以进行治疗目的。