WNT1 Function in Stem Cells in Osteogenesis Imperfecta and Craniofacial-Skeletal Tissues

WNT1 在成骨不全和颅面骨骼组织干细胞中的功能

基本信息

批准号：
10316864
负责人：
Brendan Lee
金额：
$ 57.6万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316864
关键词：
Adolescent Adult Antibodies Antibody Therapy Biological Assay Bone Injury Bone Regeneration Bone Transplantation Calvaria Cartilage Cell Differentiation process Cell Transplantation Cell model Cells Cephalic Characteristics Data Defect Development Environment Flow Cytometry Gene Expression Generations Genetic Models Goals Homeostasis Human Human Genetics In Vitro Injury KDR gene Label Life Ligands Maintenance Mediating Mesenchymal Molecular Morphology Mus Mutation Natural regeneration Neural Crest Osteoblasts Osteogenesis Osteogenesis Imperfecta Osteoporosis Patients Periosteal Cell Periosteum Phenotype Play Population Population Dynamics Regenerative research Regulation Reporting Research Proposals Role Signal Transduction Site Skeletal bone Source Specificity Surgical sutures TSC1 gene Testing Transplantation WNT Signaling Pathway WNT1 gene base bone cell motility craniofacial craniofacial bone cranium early onset healing in vivo injury and repair intravital imaging long bone migration mouse genetics mouse model novel postnatal repaired response single-cell RNA sequencing skeletal skeletal stem cell skeletal tissue stem stem cell biomarkers stem cell function stem cells tibia

项目摘要

PROJECT SUMMARY Skeletal stem cells (SSCs) are necessary for the homeostasis and repair of bone and cartilage. In craniofacial bones, periosteal skeletal stem/progenitor cells (P-SSCs) and suture mesenchymal cells play a critical role in bone homeostasis and regeneration. However, due to the restricted distribution and lack of specific markers, little is known about the function of craniofacial P-SSCs and about their specific regulatory mechanisms in homeostasis and response to bone injury. Patients with Osteogenesis Imperfecta (OI) have dysregulation of craniofacial and skeletal bone homeostasis. WNT1 mutations cause recessive OI and early onset osteoporosis and our preliminary data support altered craniofacial stem cell function. Therefore, the main objective of this research proposal is to define the in vivo characteristics and unique regulatory mechanisms of craniofacial P-SSCs, and to test if Wnt1 and α-sclerostin antibody augmentation of Wnt signaling in general are critical for these P-SSCs' response to bone injury. We hypothesize that craniofacial P-SSCs have unique molecular characteristics compared to long bone P-SSCs and that the regulation of these P-SSCs by Wnt1 is critical for craniofacial bone homeostasis, regeneration and repair. In combination with previously known SSC markers, we have newly identified selective markers for P-SSCs that enables us to isolate highly purified mouse P-SSCs and to analyze their gene expression profiles and to test their bone forming ability by transplantation of these P-SSCs into calvarial defects. We thus propose to answer the below questions in achieving the specific aims: Specific Aim 1: What are unique characteristics and function of craniofacial P- SSCs compared to long-bone P-SSCs. Specific Aim 2: How does Wnt1 signaling regulate the maintenance and function of craniofacial P-SSCs? Specific Aim 3: What are the functional consequences of loss or gain of Wnt1, and α-sclerostin therapy on craniofacial bone regeneration? These studies will identify factors that regulate the specification of SSC from different calvarial and long bone sources and the contribution of Wnt1 and effects of α-Sost treatment in regulating bone formation, and the proliferation, migration, and differentiation of neural crest derived-sutural vs. periosteal SSCs in homeostasis and repair.

项目概要骨骼干细胞（SSC）对于颅面骨和软骨的稳态和修复是必需的。骨骼、骨膜骨骼干/祖细胞 (P-SSC) 和缝线间充质细胞在然而，由于分布有限且缺乏特异性标记物，关于颅面部 P-SSC 的功能及其具体调节机制知之甚少。成骨不全 (OI) 患者的体内平衡和对骨损伤的反应存在调节失调。 WNT1 突变导致隐性成骨不全和早发。骨质疏松症和我们的初步数据支持颅面干细胞功能的改变。本研究计划的目的是确定体内特征和独特的调节机制颅面 P-SSC，并测试 Wnt1 和 α-硬化素抗体增强 Wnt 信号传导是否总体上有效我们发现颅面 P-SSC 对骨损伤的反应至关重要。与长骨 P-SSC 相比的分子特征以及 Wnt1 对这些 P-SSC 的调节与先前已知的 SSC 相结合，对颅面骨稳态、再生和修复至关重要。标记，我们新鉴定了 P-SSC 的选择性标记，使我们能够分离高度纯化的小鼠 P-SSC 并分析其基因表达谱并通过以下方法测试其骨形成能力因此，我们建议回答以下问题。实现特定目标：具体目标 1：颅面 P- 的独特特征和功能是什么 SSC 与长骨 P-SSC 的比较具体目标 2：Wnt1 信号如何调节维持。颅面 P-SSC 的功能和功能？具体目标 3：丢失或获得的功能后果是什么？ Wnt1 和 α-硬化素治疗对颅面骨再生的影响？这些研究将确定影响颅面骨再生的因素调节不同颅骨和长骨来源的 SSC 规格以及 Wnt1 的贡献 α-Sost 治疗在调节骨形成、增殖、迁移和分化中的作用神经嵴来源的小肠 SSC 与骨膜 SSC 在稳态和修复中的作用。