Wnt5a/Ror2 Signaling in Jaw Bone Development

项目总结 我们的长期目标是发现新的基于分子的疗法来调节骨骼的大小，作为一种手段 解决颅面畸形非手术治疗的需要。人们对此知之甚少 生长发育过程中控制颌骨大小的分子机制。这种知识的缺乏留下了 牵引成骨是为数不多的改变颌骨大小的干预措施之一，即使是下颌骨 众所周知，使用这种技术操作面部要比操纵长骨困难得多。治疗的程序 颌骨大小差异将从更广泛的分子和细胞机制知识库中受益匪浅 来控制下巴的大小。当前研究的目标是通过了解 颅神经沟(Cnc)构成面部和颌骨的所有元素，调节颌骨的大小。至 针对这一问题，我们建议在体内操纵CNC，这是一个高度可获得的胚胎种群。为 例如，我们可以将供者的NC移植到鸭子的宿主中，这创造了一个嵌合的Quck；然后我们移植 鸭子供体进入鹌鹑宿主，产生嵌合体对偶。利用不同的发展计划 提供了一种独特的方式来操纵计算机控制系统和邻近的宿主组织之间的信号传递 允许发现依赖于CNC的进程。一些研究小组观察了控制颌骨的骨沉积。 大小，但我们的数据表明，在NC的参与下，中胚层来源的破骨细胞的骨吸收- 衍生的骨细胞在发育的后期控制颌骨的大小。我们之前已经展示过，数控控制 颌骨大小，骨吸收由计算机控制，骨吸收控制颌骨大小。如何使用数控系统 完成如此复杂的任务，以及什么因素足以复制这种现象，是未知的。 可能的候选对象可能包括Wnt5A/ROR2非规范信号的成员和目标，因为他们是 已知在骨吸收过程中起关键作用。因此，我们假设通过调节Wnt5A/ROR2 非典范信号，cnc指导骨吸收控制颌骨大小。为了检验我们的假设，我们 提出两个相辅相成且具有高度翻译性的具体目标。具体目标1将决定机制 Cnt来源的骨细胞和中胚层来源的破骨细胞通过Wnt5A/ROR2非规范的方式发挥作用 向吸收骨发出信号，调节颌骨大小。具体目标2将决定通过什么机制 Cnc通过Wnt5A/ROR2非规范信号调控破骨细胞介导骨的活动 吸收调节颌骨大小。我们将使用功能增益和功能损失技术来识别分子 赋予计算机数控系统控制下颌骨发育能力的机制。通过确定 破骨细胞和骨细胞控制骨吸收的确切机制，未来的研究将能够 开发精确的治疗方法来控制下颌骨的发育。

PROJECT SUMMARY Our long-term goal is to discover novel molecular-based therapies for regulating the size of bone as a means to address the need for non-surgical treatments of craniofacial malformations. Little is known regarding the precise molecular mechanisms controlling jaw size during growth and development. This lack of knowledge leaves distraction osteogenesis as one of the few available interventions to change jaw size, even though bones of the face are known to be much more difficult to manipulate with this technique than long bones. Procedures to treat jaw size disparities will greatly benefit from a broader knowledge base of molecular and cellular mechanisms that control jaw size. The objective of the current study is to build toward this goal by understanding how the cranial neural crest (CNC), which forms all the elements in the facial and jaw skeletons, regulates jaw size. To address this issue, we propose to manipulate in vivo the CNC, a highly accessible embryonic population. For example, we can transplant quail donor CNC into a duck host, which creates a chimeric quck; and we transplant duck donor CNC into the quail host, generating chimeric duail. Exploiting the divergent developmental programs of quail and duck provides a unique way to manipulate signaling between CNC and adjacent host tissues and allows discovery of CNC-dependent processes. Some groups have looked at bone deposition in controlling jaw size, but our data suggest that bone resorption by mesodermally-derived osteoclasts with participation of CNC- derived osteocytes control jaw size at later stages of development. We have previously shown that CNC controls jaw size, bone resorption is controlled by CNC and that bone resorption controls jaw size. How CNC accomplishes such a complex task, and what factors are sufficient to replicate this phenomenon, is unknown. Likely candidates may include members and targets of WNT5A/ROR2 noncanonical signaling, since they are known to play critical roles during bone resorption. Therefore, we hypothesize that by modulating WNT5A/ROR2 non-canonical signaling, CNC directs bone resorption to control jaw bone size. To test our hypothesis, we propose two complementary and highly translational Specific Aims. Specific Aim 1 will determine the mechanism by which CNC-derived osteocytes and mesodermally-derived osteoclasts act via WNT5A/ROR2 non-canonical signaling to resorb bone and regulate jaw bone size. Specific Aim 2 will determine the mechanism via which CNC acts by WNT5A/ROR2 noncanonical signaling to regulate the actions of osteoclast-mediated bone resorption to regulate jaw bone size. We will employ gain- and loss-of-function techniques to identify molecular mechanisms that endow CNC with the ability to control mandibular bone development. By determining the precise mechanism of control of bone resorption by osteoclasts and osteocytes, future studies will be able to develop accurate therapies to control lower jaw bone development.