THE ROLE OF FGF RECPETORS IN LENS DEVELOPMENT

FGF 受体在晶状体发育中的作用

• 批准号: 6091454
• 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/6091454
• 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.

大多数细胞类型诱导细胞在体内分化的分子机制尚不清楚，但这些过程对人类健康的几乎所有方面都至关重要。晶状体已经成为一个越来越受欢迎的器官系统，在分子水平上解剖这些发育过程。这部分是由于它的简单性和可访问性。晶状体是少数几个在脊椎动物一生中正常持续生长的器官之一。这种生长是连续的、特征性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，这些上皮细胞被一种尚未确定的分子信号诱导分化为纤维细胞。成纤维细胞生长因子（FGFs）具有诱导晶状体上皮外植体和转基因小鼠晶状体纤维细胞分化的能力。虽然在整个发育过程中有几种fgf在眼睛中表达，但尚不清楚它们是否在晶状体纤维细胞分化中起重要作用。FGF被认为是通过FGF受体酪氨酸激酶（fgfr）发挥其大部分生物学作用的。在发育中的晶状体中有三种FGFR基因表达，这三种基因均存在零突变。FGFR1和FGFR2的纯合零突变在晶状体形成之前导致胚胎死亡，FGFR3缺失的小鼠晶状体明显正常。该项目的目的是确定fgfr是否在晶状体纤维细胞分化过程中发挥重要作用。为此，将利用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。这些小鼠将与携带FGFR1或FGFR2条件突变的小鼠杂交。这些策略应该避免传统构建的零等位基因所遇到的胚胎生存问题。除了确定单个FGFR是否对纤维细胞分化至关重要外，我们还将创建缺乏多种FGFR的小鼠，以确定单个FGFR的缺失是否可以通过其他FGFR的表达来补偿。