Wnt5a/Ror2 Signaling in Jaw Bone Development

颌骨发育中的 Wnt5a/Ror2 信号转导

• 批准号: 10545297
• 负责人: Erin Ealba Bumann
• 金额: $ 2.98万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545297
• 关键词: Address; Affect; Animals; Automobile Driving; Birds; Bone Development; Bone Growth; Bone Regeneration; Bone Resorption; Bone Resorption Inhibition; Bone Resorption Stimulation; Breathing; Calcium; Cell Line; Cells; Cephalic; Complex; Congenital Abnormality; Craniofacial Abnormalities; Data; Defect; Deposition; Development; Disease; Distraction Osteogenesis; Ducks; Elements; Embryo; Enzymes; Event; Face; Family member; Future; Gene Expression; Genes; Goals; Growth and Development function; Human; Hyperplasia; Inhibition of Matrix Metalloproteinases Pathway; Injury; Intervention; Jaw; Knowledge; Laboratories; Lead; MMP9 gene; Mandible; Mastication; Maxilla; Mediating; Molecular; Mus; Mutation; Neural Crest; Operative Surgical Procedures; Orphan; Osteoblasts; Osteoclasts; Osteocytes; Pattern; Play; Population; Procedures; Process; Quail; Quality of life; Receptor Protein-Tyrosine Kinases; Regulation; Robinow syndrome; Role; Shapes; Signal Transduction; Skeleton; Structure; TRANCE protein; Techniques; Testing; Tissues; Transplantation; Transplantation Chimera; Tumor necrosis factor receptor 11b; WNT5A gene; Western Blotting; Work; base; bisphosphonate; bone; calmodulin-dependent protein kinase II; cathepsin K; cell type; collagenase 3; craniofacial development; craniofacial structure; face bone structure; genetic technology; in vivo; knock-down; knowledge base; long bone; loss of function; malformation; member; multiphoton microscopy; novel; novel therapeutics; osteogenic; overexpression; planar cell polarity; prevent; programs; receptor; repaired; tomography; transplant model; treatment strategy

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.

项目摘要 我们的长期目标是发现基于分子的新型疗法，以调节骨骼的大小作为一种手段 解决了颅面畸形的非手术治疗的需求。关于精确的知之甚少 在生长和发育过程中控制下颌大小的分子机制。缺乏知识离开 分散成骨的作用是改变下颌大小的少数可用干预措施之一，即使 众所周知，用这种技术比长骨头更难操纵面部。治疗程序 下颌大小差异将大大受益于分子和细胞机制的更广泛的知识基础 控制下颌尺寸。当前研究的目的是通过了解 在面部和下颌骨骼中形成所有元素的颅神经rest（CNC）调节下颌大小。到 解决这个问题，我们建议在CNC中操纵体内，这是一个易于获得的胚胎人群。为了 例如，我们可以将鹌鹑供体CNC移植到鸭子宿主中，该鸭子会产生嵌合Quck。我们移植 Duck Donor CNC进入鹌鹑主持人，产生嵌合Duail。利用不同的发展计划 鹌鹑和鸭子提供了一种独特的方法来操纵CNC和相邻宿主组织之间的信号传导 允许发现与CNC相关的过程。一些小组看着控制下颌的骨沉积 大小，但我们的数据表明，中胚层衍生的破骨细胞吸收骨骼，参与CNC- 衍生的骨细胞在发育的后期阶段控制下颌大小。我们以前已经表明CNC对照 下颌大小，骨吸收由CNC控制，骨吸收控制下颌大小。 CNC如何 完成了如此复杂的任务，哪些因素足以复制这种现象，这是未知的。 可能的候选人可能包括WNT5A/ROR2非规范信号的成员和目标，因为它们是 已知在骨吸收期间起关键作用。因此，我们通过调制Wnt5a/ror2来假设 非典型信号传导，CNC指导骨吸收以控制下颌骨骼大小。为了检验我们的假设，我们 提出两个互补和高度翻译的特定目的。特定目标1将确定机制 CNC衍生的骨细胞和中层衍生的破骨细胞通过WNT5A/ROR2非传统作用 信号传导以吸收骨骼并调节下颌骨骼大小。具体目标2将确定通过的机制 CNC通过WNT5A/ROR2非规范信号传导作用，以调节破骨细胞介导的骨骼的作用 吸收以调节颌骨大小。我们将采用功能丧失技术来识别分子 赋予CNC具有控制下颌骨发育能力的机制。通过确定 骨细胞和骨细胞控制骨吸收的精确机制，未来的研究将能够 开发准确的疗法以控制下颌骨发育。