Delineating the Role of FGF Signaling and Vertebrate Heart Development

描述 FGF 信号传导和脊椎动物心脏发育的作用

• 批准号: 7636848
• 负责人: Michael WaiKok Tsang
• 金额: $ 37.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636848
• 关键词: Affect; Anterior; Bilateral; Binding; Binding Sites; Biological Assay; Biology; Biosensor; Cardiac; Cardiomegaly; Cause of Death; Cell Differentiation process; Cells; Chemicals; Chloride Ion; Chlorides; Communication; Congenital Heart Defects; Consensus Sequence; DNA; Data; Development; Differentiation and Growth; ETS Family Protein; Embryo; Embryonic Development; Embryonic Heart; Event; Exhibits; Family; Fibroblast Growth Factor; Future; Gelshift Analysis; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Heart; Heart Diseases; Heart Hypertrophy; Hematopoietic; Hereditary Disease; Human Genetics; Infant; Instruction; Investigation; Lateral; Link; Maintenance; Manuals; Maps; Mediating; Mesoderm; Molds; Molecular; Morphogenesis; Mutation; Nutritional; Organ; Organ Size; PEA3; Phase; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Play; Population; Process; Pump; Reading; Regulatory Element; Reporter; Reporting; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Staging; Stem cells; Structure; Testing; Tissues; To specify; Transcriptional Activation; Tube; Vertebrates; Writing; Zebrafish; cardiogenesis; chromatin immunoprecipitation; in vivo; loss of function; meetings; member; progenitor; promoter; public health relevance; research study; response; small molecule; small molecule libraries; transcription factor; wasting

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.

描述（由申请人提供）：先天性心脏缺陷是最常见的遗传异常之一，是婴儿死亡的主要原因。因此，心脏祖细胞如何成为胚胎中的第一个功能器官的生物学是解决的重要过程。心脏祖细胞最初是在发育时期很早就被发现的，因为胚胎中的两个细胞种群后来迁移并在中线迁移并形成心脏管。最终，通过称为形态发生的过程，这种细胞群会发展为建立功能性心脏，该功能心脏为胚胎中的营养和废物交换提供泵。该建议旨在阐明心脏形成中成纤维细胞生长因子信号传导（FGF）和（ETS）转录因子的作用。 FGF被牵涉到在心脏形成中起重要作用，并且在这种信号传导途径的组成部分中改变了胚胎发生过程中细胞通信的组成部分是人类遗传疾病的原因，这通常包括心脏缺陷。我们将测试以下假设：在心脏祖细胞规范的最早阶段需要FGF和ETS因素（AIM 1）。更重要的是，我们将确定FGF和ETS因素调节基因调节的机制（AIM 2）。此外，我们已经确定了一个小分子，即胚胎中的多活性FGF信号传导，未来的研究将决定其对心脏发育的影响（AIM 3）。了解FGF如何改变细胞命运及其控制的基因以实现这一目标，这是细胞如何模制成器官的基本问题。该建议将结合斑马鱼胚胎的胚胎学和遗传特征，以回答这些问题。公共卫生相关性。 心脏形成的手册是作为DNA中编码的一组细节指令写的。该提案的重点是如何最终成为功能性跳动器官的细胞读取和实施这些指令。具体的目标是了解ETS转录因素系列如何指导斑马鱼中的心脏发展。与心脏发展有关的另一个目标是化合物可以用来影响心脏的生长和分化的想法。为了实现这一目标，我们开发了一个斑马鱼生物传感器，该生物传感器可以报告信号活性，并确定了可以在发育过程中扩展心脏祖细胞的小分子。了解该分子如何起作用增加心脏组织是迈向开发因心脏病引起的心脏损伤的潜在治疗方法的重要一步。