CONDITIONAL MUTAGENESIS OF FIBROBLAST GROWTH FACTORS

描述(改编自申请人的描述)：先天畸形 是婴儿和儿童发病和死亡的主要原因。 掌握控制正常发育的遗传和分子程序的知识 将提高我们理解、诊断并最终预防此类事件的能力 畸形。指导肢体形成的发育程序在 胚胎的其他区域；肢体发育机制的发现 对其他器官和结构是如何形成的提供了有用的见解。 成纤维细胞生长因子(FGFs)是一种信号分子，在许多细胞中发挥作用 关键的发育途径。FGFs在人类发展中的重要性 证实了人类综合症，如Apert，Pfeiffer， Crouzon综合征是由成纤维细胞生长因子受体突变引起的。的目标是 拟议的项目是在早期确定FGF4和FGF8的作用 肢体发育。Fgf8或Fgf4在小鼠生殖系中的破坏 导致早期胚胎死亡，阻止对它们在 后期发育过程。为了避开这种杀伤力，老鼠被 产生带有条件突变的灭活的Fgf4和Fgf8 以发育调节和组织受限的方式。这些老鼠 存活，显示成纤维细胞生长因子现有模型预测不到的肢体表型 功能，并引发新的问题，这是这项建议的基础。 细胞间信号转导、细胞死亡和增殖的改变 将对导致肢体缺陷的Fgf8条件突变体进行表征。 将同时测试FGF8和FGF4可能的功能冗余 破坏肢体中的这些基因。研究Fgf8在肢体中的作用 开始时，它将在小鼠胚胎的中间中胚层中被消融。 为实现这些目标而开发的试剂也将使 突变系统是研究这些基因在人类基因组中的作用的有力工具 小鼠胚胎发育中的其他区域，包括心血管 系统。与Capecchi博士一起进行的额外研究培训以及 MCSDA将为文在寅开始她的独立研究生涯做好准备 研究脊椎动物发育的基本调控途径。 最终，这些知识将帮助我们理解这些变化是如何 无论是遗传途径还是环境途径，都会导致先天性畸形 在婴儿和儿童身上。

DESCRIPTION (Adapted from applicant's description): Congenital malformations are a major cause of morbidity and mortality in infants and children. Knowledge of the genetic and molecular programs that govern normal development will improve our ability to understand, diagnose and eventually, prevent such malformations. Developmental programs that guide limb formation operate in other regions of the embryo; discoveries in mechanisms of limb development provide useful insight into how other organs and structures are formed. Fibroblast Growth Factors (FGFs) are signaling molecules that function in many critical developmental pathways. The importance of FGFs in human development was confirmed by discoveries that human syndromes, such as Apert, Pfeiffer, and Crouzon syndromes are caused by mutations in FGF receptors. The goal of the proposed project is to determine the roles of FGF4 and FGF8 during early limb development. Disruption of either Fgf8 or Fgf4 in the germline of mice results in early embryonic lethality, preventing examination of their roles in later developmental processes. To circumvent this lethality, mice were generated bearing conditional mutations of Fgf4 and Fgf8 that were inactivated in a developmentally-regulated and tissue-restricted manner. These mice survive, display limb phenotypes not predicted by existing models of FGF function and provoke new questions that are the basis of this proposal. Alterations in intercellular signaling, cell death and proliferation that result in limb defects in Fgf8 conditional mutants will be characterized. Possible functional redundancy of FGF8 and FGF4 will be tested by simultaneous disruption of these genes in the limb. To examine the role of Fgf8 in limb initiation, it will be ablated in the intermediate mesoderm of mouse embryos. Reagents developed to achieve these aims will also make the conditional mutagenesis system a powerful tool to investigate the role of these genes in other regions of the developing mouse embryo, including the cardiovascular system. Additional research training with Dr. Capecchi and the support of a MCSDA will prepare Dr. Moon to begin her independent research career investigating fundamental regulatory pathways in vertebrate development. Ultimately, this knowledge will help us to understand how alterations in those pathways, whether genetic or environmental, result in congenital malformations in infants and children.