THE ROLE OF FGF RECPETORS IN LENS DEVELOPMENT

FGF 受体在晶状体发育中的作用

• 批准号: 6635705
• 负责人: MICHAEL L ROBINSON
• 金额: $ 34.31万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635705
• 关键词: bacteriophage P1; cell differentiation; cell growth regulation; cell proliferation; epithelium; fiber cell; fibroblast growth factor; gene deletion mutation; gene expression; genetically modified animals; growth factor receptors; laboratory mouse; lens; molecular cloning; polymerase chain reaction; protein tyrosine kinase

The molecular mechanisms by which cells are induced to differentiate in vivo is not understood for most cell types, yet these processes are fundamental to virtually every aspect of human health. The lens has become an increasingly popular organ system to dissect these developmental processes at the molecular level. This is due, in part, to its simplicity and accessibility. The lens is one of the few organs that normally continue to grow throughout the vertebrate life-span. This growth is a consequence of a continuous, characteristic pattern of proliferation and differentiation. Lens epithelial cells are the proliferative component of the lens, and these epithelial cells are induced to differentiate into fiber cells by an, as yet, undetermined molecular signal. Fibroblast growth factors (FGFs) possess the ability to induce lens fiber cell differentiation both in lens epithelial explants and in transgenic mice. While there are several FGFs expressed in the eye throughout development, it is unknown if these play an essential role in lens fiber cell differentiation. FGFs are thought to exert most of their biological effects through FGF receptor tyrosine kinases (FGFRs). There are three FGFR genes expressed in the developing lens, and null mutations exist for all three of these. Homozygous null mutations in FGFR1 and FGFR2 lead to embryonic lethality prior to lens formation, and mice deficient in FGFR3 have apparently normal lenses. The goal of this project is to determine if FGFRs play an essential role in the process of lens fiber cell differentiation. To do this, a method to delete specific gene expression in the lens epithelium will be developed using the Cre/loxP system of P1 bacteriophage. These mice will be crossed to mice carrying conditional mutations in FGFR1 or FGFR2. These strategies should avoid the problems of embryonic viability encountered with the traditionally constructed null alleles. In addition to determining if any single FGFR is essential for fiber cell differentiation, we will also create mice deficient in multiple FGFRs to determine if the loss of a single FGFR can be compensated for by the expression of other FGFRs.

对于大多数细胞类型而言，不了解细胞被诱导分化体内区分体内的分子机制，但是这些过程几乎对人类健康的各个方面都是基本的。 镜头已成为越来越流行的器官系统，可以在分子水平上剖析这些发育过程。 这部分归因于其简单性和可访问性。 镜头是通常在整个脊椎动物寿命中继续生长的少数器官之一。 这种增长是连续，特征的增殖和分化模式的结果。 晶状体上皮细胞是晶状体的增殖成分，这些上皮细胞被诱导通过尚未确定的分子信号分化为纤维细胞。 成纤维细胞生长因子（FGF）具有诱导晶状体上皮外植体和转基因小鼠的晶状体纤维细胞分化的能力。 尽管整个发育过程中都有几种FGF在眼中表达，但尚不清楚这些FGF在晶状体纤维细胞分化中是否起着至关重要的作用。 FGF被认为通过FGF受体酪氨酸激酶（FGFR）发挥其大部分生物学作用。 发育界面中有三个FGFR基因，所有三个基因都存在无效突变。 FGFR1和FGFR2中的纯合无效突变导致晶状体形成前的胚胎致死性，而缺乏FGFR3的小鼠显然具有正常的透镜。 该项目的目的是确定FGFR在晶状体纤维细胞分化过程中是否起着至关重要的作用。 为此，将使用P1噬菌体的CRE/LOXP系统开发一种删除晶状体上皮中特定基因表达的方法。这些小鼠将越过在FGFR1或FGFR2中携带条件突变的小鼠。 这些策略应避免传统构建的无等位基因遇到的胚胎生存能力的问题。 除了确定任何单个FGFR是否对于纤维细胞分化至关重要之外，我们还将创建缺乏多个FGFR的小鼠，以确定是否可以通过其他FGFR的表达来补偿单个FGFR的丢失。