Genetic Regulation of Outflow Tract Formation

流出道形成的遗传调控

基本信息

  • 批准号:
    8249046
  • 负责人:
  • 金额:
    $ 38.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-04-01 至 2016-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Formation of the outflow tract (OFT) is an essential aspect of cardiogenesis: the dimensions, orientation, and subdivision of the OFT are crucial for effective transport of blood from the heart to the periphery. OFT development initiates with the assembly of a small myocardial tube, which subsequently provides a vital foundation for OFT remodeling. Given the importance of establishing the OFT myocardium, the embryonic origins of OFT cardiomyocytes (CMs) have been of great interest. A series of studies in mouse and chick embryos have illuminated two major sources of cardiac progenitor cells, termed the first heart field (FHF) and the second heart field (SHF). Notably, the initial foundation of the OFT is built by SHF-derived CMs that are appended to the arterial pole of the heart. Although several signaling pathways have been implicated in regulating SHF differentiation, little is known about which genes function downstream of these key signals to execute OFT assembly or how the multiple relevant pathways interact to set the dimensions of the OFT. Here, we exploit the utility of the zebrafish as a model organism in order to identify novel regulators of OFT formation. Preliminary studies suggest that the zebrafish OFT, like the amniote OFT, is constructed from a population of SHF-derived CMs. Furthermore, in zebrafish, as in amniotes, Fgf signaling is required to promote the production of OFT CMs. However, it is unclear which genes act downstream of Fgf signaling to recruit the appropriate number of CMs into the OFT. Our preliminary data reveal an interesting set of genes - cell adhesion molecule 4 (cadm4), cadm3, and cadm2a - that are repressed by Fgf signaling and play essential roles in restricting the formation of OFT myocardium. These data suggest an intriguing model in which Fgf signaling drives the recruitment of OFT CMs by limiting the expression of cadm genes and thereby altering critical extracellular interactions of SHF-derived progenitor cells. In this proposal, we will test this model in detail by establishing the origins of the zebrafish OFT, deciphering the mechanisms of Cadm function, and integrating the Fgf-Cadm pathway into the context of the multiple influences that converge to define the size of the OFT. In Aim 1, we will employ fate mapping, time-lapse tracking, and assays for the timing of myocardial differentiation to determine whether the zebrafish OFT myocardium is derived from a SHF equivalent. In Aim 2, we will use loss-of-function, gain-of-function, structure-function, and biochemical analyses to test if Cadms mediate extracellular interactions that inhibit recruitment of OFT CMs. In Aim 3, we will identify signals that counterbalance the impact of the Fgf-Cadm pathway on OFT size, focusing on the roles played by Notch, Bmp, and retinoic acid signaling in limiting the dimensions of the zebrafish OFT. Together, these experiments are likely to reveal new mediators of OFT CM recruitment, to uncover a novel mechanism for regulating OFT size through modulation of extracellular interactions, and to shed light on the network of pathways that collaborate to insure an appropriate myocardial foundation for the embryonic OFT. PUBLIC HEALTH RELEVANCE: Cardiac defects are found in as many as 1 in 100 live births and 1 in 10 still births and frequently include problems with the formation of the cardiac outflow tract. Outflow tract development initiates with the assembly of a small tube of muscle, the precise dimensions of which are essential for its subsequent remodeling into a mature structure. Therefore, a better comprehension of the mechanisms controlling the initial investment of muscle into the outflow tract is likely to illuminate the causes of cardiac birth defects and may also suggest strategies for directing multipotent cells to become cardiac muscle.
描述(由申请人提供):流出道(OFT)的形成是心脏发生的一个重要方面:OFT的尺寸、方向和细分对于血液从心脏到外周的有效运输至关重要。OFT的发展始于小心肌管的组装,随后为OFT重塑提供了重要基础。鉴于建立OFT心肌的重要性,OFT心肌细胞(CM)的胚胎起源一直受到极大的关注。在小鼠和鸡胚中的一系列研究已经阐明了心脏祖细胞的两个主要来源,称为第一心区(FHF)和第二心区(SHF)。值得注意的是,OFT的初始基础是由附加到心脏的动脉极的SHF衍生的CM构建的。虽然有几种信号通路参与调节SHF分化,但对这些关键信号下游的哪些基因起作用以执行OFT组装或多个相关通路如何相互作用以设定OFT的尺寸知之甚少。 在这里,我们利用斑马鱼作为模式生物的效用,以确定新的监管机构的OFT形成。初步的研究表明,斑马鱼OFT,像斑马鱼OFT一样,是由SHF衍生的CM群体构建的。此外,在斑马鱼中,如在斑马鱼中,需要Fgf信号传导来促进OFT CM的产生。然而,目前尚不清楚哪些基因在Fgf信号传导下游发挥作用,以招募适当数量的CM进入OFT。我们的初步数据揭示了一组有趣的基因-细胞粘附分子4(cadm 4),cadm 3和cadm 2a-被Fgf信号转导抑制,并在限制OFT心肌形成中发挥重要作用。这些数据表明了一个有趣的模型,其中Fgf信号通过限制cadm基因的表达来驱动OFT CM的募集,从而改变SHF衍生的祖细胞的关键细胞外相互作用。在这项提案中,我们将通过建立斑马鱼OFT的起源,破译Cadm功能的机制,并将Fgf-Cadm途径整合到收敛于定义OFT大小的多种影响的背景下,来详细测试这个模型。在目标1中,我们将采用命运映射,时间推移跟踪,并测定心肌分化的时间,以确定斑马鱼OFT心肌是否来自SHF等效。在目标2中,我们将使用功能丧失、功能获得、结构-功能和生化分析来测试Cadms是否介导抑制OFT CM募集的细胞外相互作用。在目标3中,我们将确定抵消Fgf-Cadm途径对OFT大小的影响的信号,重点关注Notch,Bmp和视黄酸信号在限制斑马鱼OFT尺寸中所起的作用。总之,这些实验有可能揭示新的介质的OFT CM招聘,揭示一种新的机制,通过调节细胞外相互作用来调节OFT的大小,并阐明网络的途径,合作,以确保适当的心肌基础的胚胎OFT。 公共卫生相关性:在多达1/100的活产和1/10的死胎中发现心脏缺陷,并且经常包括心脏流出道形成的问题。流出道发育始于肌肉小管的组装,其精确尺寸对于其随后重塑为成熟结构至关重要。因此,更好地理解控制肌肉初始投资到流出道的机制可能会阐明心脏出生缺陷的原因,也可能建议指导多能细胞成为心肌的策略。

项目成果

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DEBORAH YELON其他文献

DEBORAH YELON的其他文献

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{{ truncateString('DEBORAH YELON', 18)}}的其他基金

Weinstein Cardiovascular Development and Regeneration Conference
韦恩斯坦心血管发育与再生会议
  • 批准号:
    10683505
  • 财政年份:
    2023
  • 资助金额:
    $ 38.72万
  • 项目类别:
Modulating Morphogenesis: Genetic Regulation of Cardiac Cell Movement in Zebrafish
调节形态发生:斑马鱼心肌细胞运动的遗传调控
  • 批准号:
    9513941
  • 财政年份:
    2016
  • 资助金额:
    $ 38.72万
  • 项目类别:
Modulating Morphogenesis: Genetic Regulation of Cardiac Cell Movement in Zebrafish
调节形态发生:斑马鱼心肌细胞运动的遗传调控
  • 批准号:
    9330923
  • 财政年份:
    2016
  • 资助金额:
    $ 38.72万
  • 项目类别:
Genetic Regulation of Outflow Tract Formation
流出道形成的遗传调控
  • 批准号:
    8452208
  • 财政年份:
    2011
  • 资助金额:
    $ 38.72万
  • 项目类别:
Genetic Regulation of Outflow Tract Formation in Zebrafish
斑马鱼流出道形成的遗传调控
  • 批准号:
    8131347
  • 财政年份:
    2011
  • 资助金额:
    $ 38.72万
  • 项目类别:
Genetic Regulation of Outflow Tract Formation
流出道形成的遗传调控
  • 批准号:
    8645715
  • 财政年份:
    2011
  • 资助金额:
    $ 38.72万
  • 项目类别:
Regulation of cardiac chamber morphogenesis in zebrafish
斑马鱼心室形态发生的调节
  • 批准号:
    7072323
  • 财政年份:
    2005
  • 资助金额:
    $ 38.72万
  • 项目类别:
Regulation of cardiac chamber morphogenesis in zebrafish
斑马鱼心室形态发生的调节
  • 批准号:
    7243460
  • 财政年份:
    2005
  • 资助金额:
    $ 38.72万
  • 项目类别:
Regulation of cardiac chamber morphogenesis in zebrafish
斑马鱼心室形态发生的调节
  • 批准号:
    7431653
  • 财政年份:
    2005
  • 资助金额:
    $ 38.72万
  • 项目类别:
Regulation of cardiac chamber morphogenesis in zebrafish
斑马鱼心室形态发生的调节
  • 批准号:
    6970395
  • 财政年份:
    2005
  • 资助金额:
    $ 38.72万
  • 项目类别:

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