FGFR2 IN SKELETOGENESIS--MUTATIONAL ANALYSIS IN MICE

FGFR2 在骨骼发生中的作用——小鼠突变分析

• 批准号: 6536320
• 负责人: HYUN-DUCK NAH-CEDERQUIST
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536320
• 关键词: apoptosis; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; craniofacial; craniosynostosis; fibroblast growth factor; flow cytometry; gene mutation; gene targeting; genetically modified animals; growth factor receptors; histology; laboratory mouse; mitogen activated protein kinase; morphometry; normal ossification; osteoblasts; osteogenesis; phenotype; receptor expression; western blottings

DESCRIPTION: (Provided by Applicant) The development of the craniofacial skeleton with its interposed sutures involves a complex process, for which molecular and cellular regulatory mechanisms are not well understood. Recent genetic studies have linked various activating mutations in the fibroblast growth factor receptor 2 (FGFR2) gene to a subset of craniosynostosis syndromes, which have in common craniofacial skeletal deformities associated with the premature fusion of cranial sutures. This suggests that FGFR2 may play important roles in skeletal and sutural development. To further develop this notion, the investigators have introduced bone-targeted mFGFR2 transgene constructs, containing an activating mutation (Pro253Arg; an Apert mutation) or a dominant negative mutation, into the mouse germ line and generated several lines of transgenic mice. Initial analyses of these mice revealed that those with an activating mutation manifested some of the typical craniofacial features of craniosynostosis patients. The mice with a dominant negative mutation also displayed a variety of skeletal abnormalities, but they were distinctively different from the craniosynostosis phenotype. Based on pro- mitogenic and anti-apoptotic responses to FGF signaling in bone cells, the investigators hypothesize that an activating FGFR2 mutation promotes proliferation of osteoblasts, while suppressing apoptosis in these cells, resulting in uncontrolled bone formation and, ultimately, suture fusion. In contrast, loss of normal FGFR activities may result in reduced bone cell proliferation with an increased rate of apopotosis, culminating in dystrophic bone and wide-open sutures. To test their hypothesis, the investigators will define the skeletal and suture phenotypes of newly generated transgenic mouse lines (Aim 1), investigate how these mutations alter bone cell functions associated with osteogenesis and suture formation (Aim 2), and finally determine whether the mitogene activated protein (MAP) kinase pathway is involved in some of the altered bone cell functions induced by FGFR2 mutations (Aim 3). Data collected from this pilot study will be used to develop hypotheses to be tested in a larger research project.

描述：（由申请人提供）颅面的发展 其插入缝合线的骨骼涉及一个复杂的过程，为此 分子和细胞调节机制尚不清楚。最近的 遗传研究已将成纤维细胞中的各种激活突变联系起来 生长因子受体2（FGFR2）基因至颅突的子集 综合症，具有常见的颅面骨骼畸形 随着颅骨缝合线的过早融合。这表明FGFR2可能 在骨骼和缝合发育中发挥重要作用。进一步发展 这个概念，研究人员引入了骨头靶向的MFGFR2转基因 构造，包含激活突变（pro253arg; apert突变） 或主要的负突变，进入小鼠种系并产生 几行转基因小鼠。这些小鼠的初步分析表明 激活突变的人表现出一些典型的颅面 颅突变患者的特征。占主导负面的小鼠 突变也显示出各种骨骼异常，但它们是 与颅突式表型不同。基于Pro- 骨细胞中FGF信号传导的有丝分裂和抗凋亡反应， 研究人员假设激活的FGFR2突变会促进 成骨细胞的增殖，同时抑制这些细胞中凋亡的同时 导致不受控制的骨形成，并最终导致缝合融合。在 对比，正常FGFR活性的丧失可能导致骨细胞减少 增殖，凋亡率增加，最终在营养不良中 骨头和宽阔的缝合线。为了检验他们的假设，调查人员将 定义新生成的转基因小鼠的骨骼和缝合表型 线（AIM 1），研究这些突变如何改变骨细胞功能 与成骨和缝合形成相关（AIM 2），最后 确定有利机激活的蛋白（MAP）激酶途径是否为 参与FGFR2突变引起的一些改变的骨细胞功能 （目标3）。该试点研究收集的数据将用于开发 在一个更大的研究项目中要测试的假设。