Delineating the Role of FGF Signaling and Vertebrate Heart Development

描述（由申请人提供）：先天性心脏病是最常见的遗传异常之一，也是婴儿死亡的主要原因。因此，心脏祖细胞如何成为胚胎中第一个功能器官的生物学是一个需要解决的重要过程。心脏祖细胞最初在发育的早期被特化为胚胎内的两个细胞群，随后迁移并在中线相遇并形成心管。最终，通过称为形态发生的过程，这群细胞进化形成一个功能性心脏，为胚胎中的营养和废物交换提供泵。该提案旨在阐明成纤维细胞生长因子信号传导（FGF）和（ETS）转录因子在心脏形成中的作用。 FGF 在心脏形成中发挥着重要作用，而该信号通路成分的突变会改变胚胎发生过程中的细胞通讯，是人类遗传疾病（通常包括心脏缺陷）的原因。我们将检验以下假设：在心脏祖细胞分化的最早阶段需要 FGF 和 ETS 因子（目标 1）。更重要的是，我们将确定 FGF 和 Ets 因子的基因调控机制（目标 2）。此外，我们还发现了一种在胚胎中使 FGF 信号过度活跃的小分子，未来的研究将确定其对心脏发育的影响（目标 3）。了解 FGF 如何改变细胞命运以及它们控制的基因是如何实现这一目标的，这是细胞如何塑造成器官的一个基本问题。该提案将结合斑马鱼胚胎的胚胎学和遗传特征来回答这些问题。公共卫生相关性。 心脏形成手册是以一组编码在 DNA 中的详细指令的形式编写的。细胞如何读取和执行这些指令，最终成为功能性跳动器官，是本提案的重点。具体来说，我们的目标是了解 ETS 转录因子家族如何指导斑马鱼的心脏发育。与心脏发育相关的另一个目标是化学化合物可用于影响心脏生长和分化的想法。为了实现这一目标，我们开发了一种斑马鱼生物传感器，可以报告信号活动，并确定了一种可以在发育过程中扩增心脏祖细胞的小分子。了解这种分子如何作用以增加心脏组织是开发针对心脏病引起的心脏损伤的潜在治疗方法的重要一步。

DESCRIPTION (provided by applicant): Congenital heart defects are one of the most common genetic anomalies, and is the leading cause of deaths in infants. The biology of how cardiac progenitor cells become the first functional organ in the embryo is therefore an important process to resolve. The cardiac progenitor cells are initially specificed very early in development as two populations of cells within the embryo that later migrate and to meet at the midline and form the heart tube. Eventually through a process known as morphogenesis this population of cells evolve to build a functional heart that provides the pump for nutritional and waste exchange in the embryo. This proposal aims to elucidate the role for the Fibroblast Growth Factor signaling (FGF) and (ETS) transcription factors in heart formation. FGFs have been implicated to play an important role in heart formation and mutations in components of this signaling pathway that alter cellular communication during embryogenesis are the cause of human genetic disease, that often includes cardiac defects. We will test the hypothesis that FGFs and ETS factors are required during the earliest phases of cardiac progenitor specification (Aim 1). More important we will determine the mechanism of gene regulation by FGFs and Ets factors (Aim 2). Further, we have identified a small molecule that hyperactives FGF signaling in the embryo and future studies will determine its affects on cardiac development (Aim 3). Understanding how FGFs can alter cell fate and the genes that they control to achieve this is a fundamental question of how cells are molded into organs. This proposal will combine the embryological and genetic features of the zebrafish embryo to answer these questions. PUBLIC HEALTH RELEVANCE. The manual for heart formation is written in as a set of detail instructions encoded in the DNA. How these instructions are read and implemented by cells that eventually become a functional beating organ is the focus of this proposal. Specifically the goal is to understand how a family of ETS transcriptional factors can direct cardiac development in the zebrafish. Another goal related to heart development is the idea that chemical compounds can be used to influence heart growth and differentiation. To reach this goal, we have developed a zebrafish biosensor that can report on signaling activity and have identified a small molecule that can expand cardiac progenitors during development. Understanding how this molecule acts to increase heart tissue is an important step towards developing potential treatment for cardiac damage caused by heart disease.