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独操作组件的适当属性。例如，在脊椎动物胚胎心脏中，有效的循环推进取决于心房和心室的独特形态、电生理和收缩特征。尽管几个世纪以来人们都认识到心房和心室心肌细胞之间的关键差异，但将细胞分配到心室特异性谱系和直接心室特异性分化的基本机制在很大程度上仍然是个谜。 我们实验室的研究重点是了解负责室命运分配的遗传途径。通过利用斑马鱼作为模式生物，我们发现 BMP 和 FGF 信号通路对心房和心室细胞数量有不同的影响，为最初建立心房和心室祖细胞池的机制提供了重要线索。此外，我们的初步数据表明，最初的心室命运决定可以是可塑的，并且存在维持分化心肌中心室特异性特征的机制。总之，我们的研究提出了一个有趣的模型，在该模型中，心脏区域的早期图案化，随后对心室特性的强化，导致正确的心室命运分配。在这里，我们建议详细评估该模型的各个方面。在目标 1 中，我们将更深入地研究负责室祖池初始建立的机制。具体来说，我们将使用命运图谱、延时跟踪、镶嵌分析和候选效应基因评估来确定 BMP 信号如何促进心房祖细胞的建立。在目标 2 中，我们将研究维持腔室特性的机制。利用腔室身份的转基因报告器、延时分析、镶嵌分析和腔室特异性调节序列的解剖，我们将测试 FGF 信号传导功能是否通过促进 nkx 基因的表达来确保维持心室腔室身份。最后，在目标 3 中，我们将利用我们发现的 4 种影响心房或心室心肌细胞生成的有趣化合物，寻求识别调节心室命运分配的新途径。 总之，我们的研究将阐明控制腔室命运分配的路径网络的新特征。从长远来看，这项工作有可能揭示心脏出生缺陷的原因并促进再生医学的创新。 公众健康相关性：有效的心脏功能取决于心房和心室的具体尺寸和功能特征。然而，负责创建不同心房和心室组织的遗传途径尚不清楚。从长远来看，更好地理解这一主题将提高我们对常见心脏出生缺陷原因的理解，并将提出指导多能细胞腔室特异性分化以达到治疗目的的策略。