Regulation of parietal bone differentiation

顶骨分化的调节

• 批准号: 7072980
• 负责人: VENKATESH GOVINDARAJAN
• 金额: $ 7.18万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072980
• 关键词: bone; craniosynostosis; genes; genetically modified animals; laboratory mouse; phenotype; role; transfection

DESCRIPTION (provided by applicant): Congenital birth defects are the leading cause of infant deaths in the United States. About 1 in 2500 children is born with craniosynostosis, a congenital birth defect that is characterized by premature fusion of the flat bones of the skull resulting in abnormal growth of the skull. Significant health problems are associated with craniosynostosis syndromes and surgical intervention is the only recourse for children with this problem. In order to develop alternative strategies for treatment of these defects, a clear understanding of bone development is essential. Bones form by intramembranous (direct formation of bone) or by endochondral (initial formation of cartilage and later replacement by bone) ossification. How cell-intrinsic factors, such as transcription factors, regulate these two differentiation programs have been studied in detail. However, extrinsic signals that initiate these alternate modes of development have not been clearly defined. Our long-term goal is to understand how extracellular signals, such as FGFs (fibroblast growth factor), regulate early cell fate decisions that determine the choice between endochondral and intramembranous ossification in vivo. To this end, we will use a transgenic line (OVE1070) we have generated that shows an altered pattern of differentiation of the parietal bones of the skull. In these mice, the cranial mesenchymal cells that form the parietal bones switch from intramembranous to endochondral ossification. Our preliminary results support the hypothesis that this switch in the parietal bone differentiation program is due to Fgf9 transgene expression in the cranial mesenchymal precursors. The Specific Aim will test this hypothesis by replication of the OVE1070 phenotype by generation of transgenic mice with targeted expression of Fgf9 in the cranial mesenchymal precursors. As an outcome of the proposed investigations, we expect to elucidate an early (and a novel) role for FGF signaling in regulation of early cell fate decisions involved in skeletal growth and differentiation. As mutations in FGF receptors and impaired FGF signaling have been shown to be associated with craniosynostosis in humans, a clear understanding of the ways in which FGF signaling modulates skeletal differentiation is critical for understanding the causes for craniosynostosis and defining possible targets for therapy.

描述（由申请人提供）：先天性先天缺陷是美国婴儿死亡的主要原因。大约2500名儿童出生时患有颅内突变病，这是一种先天性的先天缺陷，其特征是头骨的扁平骨头过早融合，导致头骨异常生长。重大的健康问题与颅突式综合症有关，手术干预是该问题儿童的唯一诉讼。为了制定治疗这些缺陷的替代策略，对骨骼发育的清晰了解至关重要。由膜内（骨的直接形成）或软骨内（软骨的初始形成，然后被骨骼替换）形成骨骼。如何详细研究了细胞中的因素（例如转录因子）调节这两个分化程序。但是，尚未明确定义启动这些替代发展模式的外部信号。我们的长期目标是了解细胞外信号（例如FGF（成纤维细胞生长因子））如何调节早期细胞命运决策，这些决策决定了体内软骨内侧和膜内骨化之间的选择。为此，我们将使用一条转基因线（OVE1070），我们生成的它显示了颅骨顶骨的分化模式的改变。在这些小鼠中，形成顶骨的颅间充质细胞从膜内骨内骨化转变为内侧软骨。我们的初步结果支持以下假设：顶骨分化程序中的这种转换是由于颅间充质前体中的FGF9转基因表达引起的。具体的目的将通过在颅间充质前体中具有靶向FGF9的靶向表达的转基因小鼠来复制OVE1070表型来检验这一假设。作为拟议研究的结果，我们希望阐明FGF信号在调节骨骼生长和分化涉及的早期细胞命运决策中的早期（新颖）作用。由于已经证明FGF受体中的突变和FGF信号受损与人类的颅突变有关，因此对FGF信号调节骨骼分化的方式清楚地理解了对理解颅骨性颅骨伴随颅骨的原因至关重要。