Morphogenetic Control of Cartilage and Bone Development

软骨和骨发育的形态发生控制

• 批准号: 7432429
• 负责人: ANDREW P. MCMAHON
• 金额: $ 40.87万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7432429
• 关键词: Accidents; Address; Adult; Biological Models; Bone Development; Bone and Cartilage Funding; Cartilage; Cells; Cephalic; Chondrocytes; Clinical; Code; Computer Simulation; Development; Differentiation and Growth; Disease; Embryo; Etiology; Event; Evolution; Excision; Face; Feedback; Foxes; Gene Expression; Gene Transfer Techniques; Genes; Genetic; Genetic Models; Goals; Growth; Human; Lead; Ligands; Maps; Mediating; Molecular; Movement; Mus; Neural Crest; Neural Crest Cell; Numbers; Osteoblasts; Osteogenesis; PTHLH gene; Pathway interactions; Pattern; Play; Primordium; Principal Investigator; Range; Regulation; Repression; Riots; Role; Series; Signal Transduction; Skeletal Development; Skeletal system; Skeleton; Staging; Structure; Surface; Therapeutic; Transcriptional Regulation; Work; base; bone; design; expectation; genetic manipulation; insight; limb bone; long bone; mutant; novel; parathyroid hormone-related protein; programs; rib bone structure; skeletal disorder; spine bone structure

Understanding the molecular and cellular events which lead to normal bone formation is an essential prerequisite for understanding the aetiology of skeletal disorders in humans. Further, these insights will enable the design of rational, information-based therapeutic approaches for treating pathological or accidental damage to the skeleton. This proposal sets out to explore the mechanisms underlying key aspects of mammalian skeletogenesis using the mouse as a genetic model. Aim 1 will examine Ihh's regulatory role in the endochondral skeleton. We will address the significance of Gli3-repression in Ihh signaling and the direct or indirect role of Ihh in regulating PTHrP expression, and thereby chondrocyte maturation. Finally, we will use transcriptional profiling to identify putative targets of Ihh's multiple actions in endochondral skeletal development. Aim 2 will address the role of Ihh and Wnt signaling in the osteoblast lineage through a step-wise series of genetic manipulations. Aim 3 will fate map cranial neural crest skeletal precursors as a first step towards examining the relationship between a putative "Fox-code" and specific skeletal structures of the mammalian face.

了解导致正常骨形成的分子和细胞事件是理解人类骨骼疾病病因学的必要前提。此外，这些见解将有助于设计合理的、基于信息的治疗方法来治疗骨骼的病理性或意外损伤。本研究以小鼠为遗传模型，探讨哺乳动物骨骼形成的关键机制。目的1将研究Ihh在软骨内骨骼中的调节作用。我们将讨论gli3抑制在Ihh信号传导中的意义，以及Ihh在调节PTHrP表达从而促进软骨细胞成熟中的直接或间接作用。最后，我们将使用转录谱来确定Ihh在软骨内骨骼发育中的多种作用的假定目标。目的2将通过一系列循序渐进的遗传操作来解决Ihh和Wnt信号在成骨细胞谱系中的作用。目标3将绘制颅神经嵴骨骼前体的命运图，作为研究假定的“狐狸代码”与特定神经细胞之间关系的第一步