Dissecting the Genetics of Craniofacial Skeletogenesis

剖析颅面骨骼发生的遗传学

• 批准号: 6936802
• 负责人: BRIAN Frank EAMES
• 金额: $ 4.72万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936802
• 关键词: biomarker; bone development; craniofacial; developmental genetics; fluorescent dye /probe; gene interaction; gene mutation; genetic regulation; genetic screening; genetically modified animals; nonmammalian vertebrate embryology; postdoctoral investigator; transcription factor; zebrafish

DESCRIPTION (provided by applicant): The ability to induce therapeutically bone or cartilage formation would allow clinicians to treat a variety of congenital skeletal syndromes or accelerate bone fracture healing. As a model for such applications, craniofacial skeletogenesis involves the specification of cell fates in a tightly regulated spatiotemporal fashion. In this proposal, three sets of experiments will challenge the plasticity behind cell specification during development of the cranial skeleton, using both directed and unbiased approaches to identify and characterize factors that regulate skeletal cell fates in vivo. In both gain and loss of function approaches, embryonic cells that are known to give rise to specific tissue types (e.g., bone) in the zebrafish hyoid skeleton will be injected with compounds that modify expression of the skeletogenic transcription factors Sox9a, SoxQb, Runx2a, and Runx2b. Using transgenic methodologies combined with single cell clonal analyses, expression of these factors will be tightly correlated with ultimate cell fates. Finally, an unbiased genetic screen for zebrafish skeletal mutants will identify novel factors regulating skeletal cell specification. In total, this proposal will clarify at the cellular level the molecular mechanisms regulating skeletogenesis.

描述（由申请人提供）：诱导治疗性骨或软骨形成的能力将使临床医生能够治疗各种先天性骨骼综合征或加速骨折愈合。作为此类应用的模型，颅面骨骼生成涉及以严格调节的时空方式对细胞命运的规范。在此提案中，使用定向和无偏的方法来识别和表征体内调节骨骼细胞命运的因素。在功能方法的增益和丧失中，已知会导致斑马鱼舌骨骼中特定的组织类型（例如骨骼）的胚胎细胞注射，以修饰骨骼发育因子Sox9a的表达SOX9A，SOXQB，SOXQB，RUNX2A和RUNX2B。使用转基因方法与单细胞克隆分析结合使用，这些因素的表达将与最终细胞命运密切相关。最后，斑马鱼骨骼突变体的无偏遗传筛选将确定调节骨骼细胞规范的新因素。总的来说，该建议将在细胞水平上阐明调节骨骼生成的分子机制。