Delineating the Role of FGF Signaling and Vertebrate Heart Development

描述(申请人提供)：先天性心脏缺陷是最常见的遗传异常之一，也是导致婴儿死亡的主要原因。因此，心脏前体细胞如何成为胚胎中第一个功能器官的生物学问题是一个需要解决的重要过程。心脏祖细胞最初被认为是胚胎内的两组细胞，它们后来迁移并在中线相遇，形成心管。最终，通过一个被称为形态发生的过程，这些细胞群体进化成一个功能强大的心脏，为胚胎中的营养和废物交换提供泵。本研究旨在阐明成纤维细胞生长因子信号转导和转录因子在心脏形成中的作用。FGFs被认为在心脏形成中发挥重要作用，而在胚胎发育过程中改变细胞通讯的这一信号通路组件的突变是人类遗传病的原因，通常包括心脏缺陷。我们将检验这一假设，即FGFs和ETS因子在心脏祖细胞规范的早期阶段是必需的(目标1)。更重要的是，我们将确定FGFs和ETS因子对基因调控的机制(目标2)。此外，我们已经确定了一个小分子，它能在胚胎中激活成纤维细胞生长因子信号，未来的研究将确定它对心脏发育的影响(目标3)。了解FGFs如何改变细胞命运及其控制的基因实现这一目标，是细胞如何塑造成器官的一个基本问题。这项提议将结合斑马鱼胚胎的胚胎学和遗传学特征来回答这些问题。与公共卫生相关。心脏形成手册是作为DNA中编码的一套详细说明写成的。这些指令是如何被最终成为功能跳动器官的细胞阅读和执行的，这是这项提案的重点。具体地说，目标是了解ETS转录因子家族如何指导斑马鱼的心脏发育。另一个与心脏发育相关的目标是化合物可以用来影响心脏的生长和分化。为了达到这一目标，我们开发了一种斑马鱼生物传感器，它可以报告信号活性，并已经确定了一种小分子，可以在发育过程中扩大心脏祖细胞。了解这种分子是如何作用于增加心脏组织的，是开发治疗心脏病造成的心脏损伤的潜在疗法的重要一步。

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.