Mechanical and Transcriptional Roles for Primary Cilia during Heart Development

原发纤毛在心脏发育过程中的机械和转录作用

基本信息

  • 批准号:
    10677718
  • 负责人:
  • 金额:
    $ 3.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Abstract: Congenital heart defects (CHD) are the most common birth defects, affecting 1% of all live births. Of the known genetic contributors to CHD, the pathogenic mechanism is undetermined for most. Our lab has identified de novo mutations in kruppel-like factors 2 and 4 (KLF2, 4) in CHD patients presenting with hypoplastic left heart syndrome (HLHS). Klf2 and 4 are mechanosensitive transcription factors that regulate endothelial to mesenchymal transition (EndoMT), a process necessary for cushion (heart valve progenitor) development. Understanding how EndoMT is spatially and temporally controlled by mechanical modulation of Klf2/4 will provide insights into the heart valve defects present in HLHS patients. Our lab has implicated primary cilia (non-motile, rod-like mechanosensors) on the endocardium (EC) in cardiogenesis beyond their known role in left-right asymmetry. However, whether EC primary cilia transduce mechanical signals into regulation of Klf2/4 during cushion development has yet to be shown. The goal of this proposal is to discover the relationship between mechanical forces, EC primary cilia and Klf2/4 during heart cushion formation in vivo. Based on my preliminary results, the overall hypothesis of this proposal is that EC primary cilia link mechanical forces and Klf2/4 transcription in a Ca2+ and cytoskeletal-dependent manner during endocardial cushion formation in vivo. To address this hypothesis, we will utilize both mouse and zebrafish models. Mouse hearts are more comparable to humans (zebrafish have two chambers), but the genetic programs governing cardiogenesis are conserved. Events that may be lost in static mouse samples can instead be observed using live zebrafish in time-lapse microscopy due to their optical clarity and external development. Aim 1 will investigate how EC primary cilia and Klf2/4 expression change spatially over heart cushion development, utilizing in situ hybridization and immunofluorescence in mice, and various transgenic lines marking endocardium, cilia, and the promoter regions of Klf2/4 in live zebrafish. Aim 2 will test whether Klf2/4 depend on cilia, ciliary Ca2+ and/or mechanical forces through use of various mutant backgrounds, such as Ift20 and Kif3a (cilia KOs), Ncx/silent heart morpholino (heartbeat KO, mouse and zebrafish, respectively), and Pkd2 (ciliary Ca2+ KO). Our data provides insight into the mechanism controlling Klf2/4 mechanosensitivity during heart cushion formation, and highlight a ciliary role as mechanosensors during cardiogenesis. This proposal addresses the NIH-NHLBI's objectives 1 and 2 in regards to investigating the genetic and mechanical mechanism behind the valve defects present in many CHD patients. Our findings could also lead to treatments to ameliorate the progressive valve dysfunction experienced by many CHD patients. My use of live, whole- mount imaging will extend beyond the observations possible in static, fixed embryos and bring a rare perspective of ciliary-dependent transcription in vivo. The role of mechanical forces during development is a rapidly expanding field, and our results will contribute to both a basic and translational biological perspective.
摘要:先天性心脏缺陷(CHD)是最常见的先天缺陷,影响了所有活产的1%。的 对于大多数人来说,已知的遗传因素是冠心病的,致病机制是不确定的。我们的实验室有 鉴定出类似Kruppel样因子2和4(KLF2,4)的从头突变的冠心病患者 左心脏综合征(HLHS)。 KLF2和4是调节的机械敏感转录因子 内皮到间充质转变(endomt),这是缓冲(心脏瓣膜祖细胞)所需的过程 发展。了解如何通过机械调制在空间和时间上控制胚胎 KLF2/4将提供有关HLHS患者存在的心脏瓣膜缺陷的见解。我们的实验室牵涉 心脏发生的内膜(EC)上的原发性纤毛(非运动,类似杆状的机械传感器) 在左右不对称中已知的作用。但是,EC主要的纤毛纤毛机械信号是否 坐垫发育过程中KLF2/4的调节尚未显示。该提议的目的是发现 在体内心垫形成期间,机械力,EC原发性纤毛和KLF2/4之间的关系。 基于我的初步结果,该提案的总体假设是EC主要纤毛链接 机械力和KLF2/4在Ca2+和细胞骨架依赖性方式中转录。 体内心内膜垫形成。为了解决这一假设,我们将同时利用鼠标和斑马鱼 型号。鼠标心脏更像人类(斑马鱼有两个腔室),但是遗传 控制心脏病的程序是保存的。在静态鼠标样品中可能丢失的事件可以 相反,由于其光学清晰度和外部,可以在延时显微镜中使用活斑马鱼观察到 发展。 AIM 1将研究EC主要纤毛和KLF2/4表达如何在空间上改变心脏 垫子发育,利用小鼠的原位杂交和免疫荧光以及各种转基因 在活斑马鱼中标记KLF2/4的启动子区域的线条线。 AIM 2将测试是否 KLF2/4取决于纤毛,睫状Ca2+和/或机械力,通过使用各种突变背景,例如 如IFT20和KIF3A(Cilia Kos),NCX/Silent Heart Morpholino(分别 和PKD2(纤毛CA2+ KO)。我们的数据提供了控制KLF2/4机械强度的机制 在心脏垫形成期间,并突出了心脏发生过程中的机械传感器的睫状作用。这 提案针对NIH-NHLBI的目标1和2在研究遗传和机械方面 许多CHD患者存在瓣膜缺陷背后的机制。我们的发现也可能导致治疗 改善许多CHD患者经历的进行性瓣膜功能障碍。我对现场直播的使用 安装成像将超出静态,固定胚胎的观察结果,并带来罕见 体内睫状依赖性转录的透视。机械力在开发过程中的作用是 快速扩展的领域,我们的结果将有助于基本和转化的生物学观点。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A change of heart: new roles for cilia in cardiac development and disease.
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Kathryn Berg其他文献

Kathryn Berg的其他文献

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{{ truncateString('Kathryn Berg', 18)}}的其他基金

Mechanical and Transcriptional Roles for Primary Cilia during Heart Development
原发纤毛在心脏发育过程中的机械和转录作用
  • 批准号:
    10231571
  • 财政年份:
    2021
  • 资助金额:
    $ 3.25万
  • 项目类别:
Mechanical and Transcriptional Roles for Primary Cilia during Heart Development
原发纤毛在心脏发育过程中的机械和转录作用
  • 批准号:
    10543038
  • 财政年份:
    2021
  • 资助金额:
    $ 3.25万
  • 项目类别:

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