Genetic Regulation of Cardiac Patterning in Zebrafish

斑马鱼心脏模式的遗传调控

• 批准号: 7388856
• 负责人: DEBORAH YELON
• 金额: $ 33.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388856
• 关键词: Animal Model; Cardiac; Cardiac Myocytes; Cardiomegaly; Cells; Characteristics; Collection; Comprehension; Congenital Abnormality; Data; Depth; Development; Embryo; Embryonic Development; Exhibits; Forelimb; Gene Expression; Generations; Genes; Genetic; Goals; Heart; Heart Atrium; Histologic; Maps; Mediator of activation protein; Modeling; Molecular; Mutation; Myelogenous; Numbers; Organ; Organogenesis; Pathway interactions; Pattern; Population; Production; Purpose; Regulation; Relative (related person); Research; Research Personnel; Resolution; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Techniques; Testing; Therapeutic; Tretinoin; Ventricular; Zebrafish; cardiogenesis; gain of function; improved; insight; progenitor; programs; research study; size

DESCRIPTION (provided by applicant): Organogenesis begins with the specification of the appropriate quantity and variety of organ progenitor cells. During heart development, the generation of specific numbers and types of progenitor cells is necessary for the formation of cardiac chambers of the appropriate size and characteristics. In its simplest form, the embryonic vertebrate heart is composed of two major chambers, a ventricle and an atrium. Ventricular and atrial cardiomyocytes differ morphologically, histologically, and physiologically. The intrinsic differences between chambers are critical for effective cardiac function, but the mechanisms responsible for production of the correct numbers of ventricular and atrial cardiomyocytes are not well understood. The long-term goal of our research is to identify the genetic pathways that regulate two crucial aspects of cardiomyocyte production: the specification of a proper number of cardiac progenitors and their allocation into ventricular and atrial populations. Using the zebrafish as a model organism, we have assembled a collection of mutations that disrupt cardiomyocyte production. Additionally, we have established high- resolution fate mapping techniques capable of distinguishing whether and how specific genes regulate cardiac fate assignment. This combination of approaches has yielded several insights regarding the mechanisms that define and divide the cardiac progenitor pool. Most notably, we have discovered an essential early function of retinoic acid (RA) signaling. Reduction of RA signaling produces an excess of cardiomyocytes, via fate transformations that increase the number of cardiac progenitor cells. Thus, RA has a potent repressive role during cardiac specification. Here, we propose to delve deeper into the repressive influence of RA signaling and to investigate an independent pathway with a previously undescribed role in restricting cardiac specification. Additionally, we will broaden our scope to include the analysis of signaling pathways hypothesized to control the relative proportions of ventricular and atrial progenitors. Our specific aims are: (1) to determine how RA signaling restricts cardiac specification, (2) to demonstrate how endothelial and myeloid specification pathways repress cardiac developmental potential, (3) to test the role of Bmp signaling in promoting atrial cardiomyocyte production, and (4) to identify the roles of Fgf signaling during ventricular cardiomyocyte production. Together, these studies will illuminate new features of the network of pathways controlling cardiomyocyte production. In the long term, this information will improve our understanding of the causes of common cardiac birth defects and suggest strategies for the therapeutic manipulation of cardiac stem cells.

描述（由申请人提供）：器官发生始于器官祖细胞的适当数量和种类的规格。在心脏发育过程中，特定数量和类型的祖细胞的产生对于形成适当大小和特征的心腔是必要的。在最简单的形式中，胚胎脊椎动物的心脏由两个主要腔室组成，心室和心房。心室和心房心肌细胞在形态学、组织学和生理学上不同。心室之间的内在差异对于有效的心脏功能至关重要，但负责产生正确数量的心室和心房心肌细胞的机制尚未得到很好的理解。我们研究的长期目标是确定调节心肌细胞产生的两个关键方面的遗传途径：指定适当数量的心脏祖细胞及其分配到心室和心房群体。使用斑马鱼作为模式生物，我们已经收集了一系列破坏心肌细胞生产的突变。此外，我们已经建立了高分辨率的命运定位技术，能够区分特定基因是否以及如何调节心脏命运分配。这种方法的组合已经产生了一些关于定义和划分心脏祖细胞库的机制的见解。最值得注意的是，我们已经发现了维甲酸（RA）信号传导的重要早期功能。RA信号的减少通过增加心脏祖细胞数量的命运转化产生过量的心肌细胞。因此，RA在心脏特化过程中具有强有力的抑制作用。在这里，我们建议深入研究RA信号的抑制作用，并研究一个独立的途径，以前未描述的作用，限制心脏规格。此外，我们将扩大我们的范围，包括信号通路的分析假设控制心室和心房祖细胞的相对比例。我们的具体目标是：（1）确定RA信号传导如何限制心脏特化，（2）证明内皮和骨髓特化途径如何抑制心脏发育潜能，（3）测试Bmp信号传导在促进心房心肌细胞产生中的作用，以及（4）鉴定Fgf信号传导在心室心肌细胞产生中的作用。这些研究将共同阐明控制心肌细胞产生的途径网络的新特征。从长远来看，这些信息将提高我们对常见心脏出生缺陷原因的理解，并为心脏干细胞的治疗操作提出策略。