SIGNAL TRANSDUCTION PATHWAYS IN THE EYE OF TRANSGENIC MICE

转基因小鼠眼中的信号转导途径

• 批准号: 6290117
• 负责人: ANA B CHEPELINSKY
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290117
• 关键词: biological signal transduction; cell cycle proteins; cell differentiation; crystallins; developmental genetics; enzyme activity; eye; fibroblast growth factor; gene expression; genetic promoter element; genetically modified animals; interferon gamma; laboratory mouse; laboratory rat; lens; protein kinase; transcription factor; transfection

The goal of this project is to understand how aberrant lens expression of two activators of gene transcription by signal transduction pathways, gamma interferon(IFN) and FGF-3, perturb normal eye development in transgenic mice. Constitutive expression of IFN gamma in the lens of transgenic mice provides a useful model to study cytokine signaling during embryonic eye development. In collaborative studies with Dr. Charles Egwuagu (Laboratory of Immunology, NEI) we developed transgenic mice and rats with constitutive expression of IFN gamma, which became useful animal models for the study of experimental autoimmune uveitis and anterior uveitis. This ongoing collaboration allowed us to study how constitutive expression of IFN gamma and its induction and activation of IFN gamma-inducible transcriptional factors in the eye altered the developmental fate of cells destined to become lens fiber cells by altering the pattern of lens gene expression. Furthermore, these studies led us to discover the expression of members of the IRF family of transcription factors in the lens. These findings have important implications for understanding signal transduction pathways in the lens.In collaboration with Drs. Paul Overbeek (Baylor College of Medicine) and Dr. Michael Robinson (Ohio State University) we developed transgenic mice with ectopic expression of FGF-3 in their lenses, which showed premature differentiation of their lens epithelia. We found that ectopic expression of secreted FGF-3 in the lens induces ectopic expression of the cyclin dependent kinase inhibitor p57/Kip2 gene, specifically expressed at the equatorial region of the wild type lens, followed by withdrawal from the cell cycle and differentiation of the entire lens epithelium. Taken together, the results obtained with both transgenes indicate that perturbation of gene transcription by ectopic activation of protein kinases involved in signal transduction pathways and the aberrant activation of transcription factors results in altered eye differentiation. - signal transduction, transgenic mice, eye gene expression, eye differentiation

该项目的目的是了解通过信号转导途径，伽马干扰素（IFN）和FGF-3，在转基因小鼠中扰动正常眼发育的基因转录的异常透镜表达。转基因小鼠晶状体中IFN伽马的组成型表达为研究胚胎眼发育过程中的细胞因子信号传导提供了有用的模型。在与Charles Egwuagu博士（NEI免疫学实验室）的合作研究中，我们开发了具有IFN GAMMA组成型表达的转基因小鼠和大鼠，这成为研究实验性自身免疫性葡萄膜炎和前葡萄膜炎的有用动物模型。这种持续的合作使我们能够研究IFN伽马的本构​​表达及其在眼中IFNγ诱导的转录因子的诱导和激活如何通过改变晶状体基因表达的模式来改变注定成为晶状体纤维细胞的细胞的发育命运。此外，这些研究使我们发现了镜头中IRF转录因子家族成员的表达。这些发现对于理解镜头中的信号转导途径具有重要意义。 Paul Overbeek（贝勒医学院）和迈克尔·罗宾逊（Michael Robinson）（俄亥俄州立大学），我们开发了转基因小鼠，其镜头中FGF-3异位表达，这表明其镜头上皮的过早差异化。我们发现，分泌的FGF-3在晶状体中的异位表达诱导细胞周期蛋白依赖性激酶抑制剂p57/kip2基因的异位表达，该基因在野生型晶状体的赤道区域中表达，然后从野生型晶状体的赤道区域表达，然后从整个晶状体上皮的细胞周期中退出。综上所述，两种转基因获得的结果表明，通过参与信号转导途径的蛋白激酶的异位激活基因转录的扰动，转录因子的异常激活导致眼睛分化改变。 - 信号转导，转基因小鼠，眼基因表达，眼睛分化