The Role of FGF Receptors in Lens Development

FGF 受体在晶状体发育中的作用

基本信息

批准号：
7454258
负责人：
MICHAEL L ROBINSON
金额：
$ 33.78万
依托单位：
MIAMI UNIVERSITY OXFORD
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7454258
关键词：
Address Alleles Alternative Splicing Apoptosis Binding Binding Sites Biochemical Pathway Biology Blindness Breeding Cataract Cell Cycle Cell Differentiation process Cell Survival Cells Chimera organism Crystalline Lens Cultured Cells Development Disease Docking Embryo Epithelial Cells Epithelium FGF1 gene FGFR1 gene FRS2 gene Family Fiber Fibroblast Growth Factor Fibroblast Growth Factor Receptors Genes Grant Growth Factor Growth Factor Receptors Human In Vitro Kinase Family Gene Length Lens Fiber Lens Placodes Life Ligands Malignant Neoplasms Mediating Modification Molecular Mus Mutation Neurotrophic Tyrosine Kinase Receptor Type 3 Organism Pathway interactions Phase Phenotype Play Process Protein Isoforms Protein Tyrosine Kinase Proteins Public Health Purpose Receptor Gene Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Research Personnel Role Signal Pathway Signal Transduction Signal Transduction Pathway Staging Testing Thinking Transgenic Mice Tyrosine Phosphorylation Vesicle Withdrawal design embryonic stem cell fiber cell human FRS2 protein in vivo lens lens induction member mutant phospholipase C gamma prevent programs receptor response

项目摘要

DESCRIPTION: The regulation of cell differentiation, proliferation and apoptosis is a fundamental requirement for any living multicellular organism. The fibroblast growth factor (FGF) family, in both mice and humans, consists of genes encoding 22 different ligands and four tyrosine kinase receptors (FGFR1-4). FGF stimulation has been shown to induce survival, proliferation and differentiation in cells of the ocular lens. Transgenic mice over-expressing several different FGF ligands undergo ectopic differentiation of the lens epithelium. Furthermore, conditional deletion of Fgfr genes leads to lens abnormalities depending on which receptor is deleted and what stage of lens development the deletion takes place. Deletion of Fgfr2 alone during the lens placode stage does not prevent lens fiber differentiation, but does cause a slight delay in lens cell cycle withdrawal and compromises lens cell survival. In contrast, on an Fgfr3 null background, lens fiber differentiation can be prevented by simultaneous deletion of Fgfr1 and Fgfr2 at the lens vesicle stage. Therefore, FGFs and FGFRs play a vital and fundamental role in lens biology and are absolutely required for lens fiber differentiation. The purpose of this application is to examine the relevant biochemical pathway, subsequent to Fgfr stimulation, that mediates FGF-induced responses in the lens. The hypothesis to be tested is that the major pathway by which Fgfrs mediate lens fiber differentiation is through the activation of the intermediate docking protein FRS2alpha. This hypothesis will be tested by (1) direct modification of the mouse Fgfr2 locus to create mutations designed to a) disrupt interaction with FRS2alpha, b) disrupt interaction with PLCgamma and c) create a chimeric receptor with an intracellular domain from TrkC (a receptor that also induces the activation of FRS2alpha) and testing to see if these different mutant Fgfr2 genes can or can not support a fiber differentiation response in the absence of functional Fgfr1 and Fgfr3 receptors; (2) making a conditional mutation in FRS2alpha and inducing lens-specific loss of this gene; (3) testing the ability of TrkC to induce a fiber differentiation response in lens epithelial cells in vivo. This application is relevant to public health because cataract remains the most frequent worldwide cause of blindness and FGF/FGFR signaling plays an essential role in lens development. FGF signaling also plays fundamental roles in many disease processes including cancer, but the molecular details of how FGFs elicit their effects are not fully resolved.

描述：细胞分化，增殖和凋亡的调节是任何生物多细胞生物的基本要求。小鼠和人类的成纤维细胞生长因子（FGF）家族由编码22种不同的配体和四个酪氨酸激酶受体（FGFR1-4）的基因组成。 FGF刺激已显示可诱导眼镜细胞的生存，增殖和分化。过表达几种不同FGF配体的转基因小鼠会经历晶状体上皮的异位分化。此外，FGFR基因的条件缺失会导致晶状体异常，具体取决于删除的受体以及透镜发育的哪些阶段发生。单独的FGFR2在晶状体位置阶段单独删除并不能阻止透镜纤维分化，但确实会导致晶状体细胞周期撤离的略有延迟，并损害透镜细胞的存活。相比之下，在FGFR3无效背景下，可以通过在晶状体囊泡阶段同时删除FGFR1和FGFR2来防止透镜纤维分化。因此，FGF和FGFR在晶状体生物学中起着至关重要的作用，并且绝对是晶状体纤维分化所必需的。本应用的目的是检查FGFR刺激后的相关生化途径，该途径介导了晶状体中FGF诱导的反应。要测试的假设是，FGFR介导透镜纤维分化的主要途径是通过激活中间停靠蛋白FRS2Alpha的激活。该假设将通过（1）直接修改鼠标FGFR2座位，以创建旨在a）a）破坏与FRS2Alpha的相互作用的突变，b）破坏与Plcgamma和C的相互作用，与plcgamma和c）创建与TRKC的细胞内域中的嵌合受体（也可以诱导FG的活性FG），并诱导了fg frs2alppha的激活或测试，该杂物是否诱导了这些群体。在没有功能性FGFR1和FGFR3受体的情况下支持纤维分化反应；（2）在FRS2Alpha中进行条件突变，并诱导该基因的透镜特异性损失；（3）测试TRKC在体内晶状体上皮细胞中诱导纤维分化反应的能力。该应用与公共卫生有关，因为白内障仍然是世界盲目的最常见原因，而FGF/FGFR信号在晶状体开发中起着至关重要的作用。 FGF信号传导在包括癌症在内的许多疾病过程中也起着基本作用，但是FGF如何引起其作用的分子细节尚未完全解决。