Morphogenetic Control of Cartilage and Bone Development

了解导致正常骨形成的分子和细胞事件是了解人类骨骼疾病病因的必要前提。此外，这些见解将使设计合理的，基于信息的治疗方法，用于治疗病理或意外损伤的骨骼。该建议以小鼠为遗传模型，探索哺乳动物骨骼发生关键方面的机制。目的1将检查Ihh的调节作用，在软骨内骨骼。我们将讨论Gli 3-阻遏在Ihh信号传导中的意义，以及Ihh在调节PTHrP表达中的直接或间接作用，从而促进软骨细胞成熟。最后，我们将使用转录分析来确定Ihh的多个行动的推定目标内软骨骨骼发育。目的2将通过一系列逐步的遗传操作来解决Ihh和Wnt信号在成骨细胞谱系中的作用。目的3将脑神经嵴骨骼前体的命运图作为检查推定的“狐狸代码”和特定的 哺乳动物面部的骨骼结构。

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.