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学的基本前提。此外，这些洞察力将使设计合理的、基于信息的治疗方法来治疗骨骼的病理或意外损伤成为可能。这项建议旨在利用小鼠作为遗传模型来探索哺乳动物骨骼发生的关键方面的潜在机制。目标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信号中的意义，以及IHH在调节PTHrP表达从而调控软骨细胞成熟中的直接或间接作用。最后，我们将使用转录图谱来确定IHH在软骨内骨骼发育中的多种作用的假定靶点。目标2将通过一系列循序渐进的遗传操作解决IHH和Wnt信号在成骨细胞谱系中的作用。Aim 3将绘制颅神经脊骨前体的命运图，作为研究假定的“狐狸密码”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.