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

• 批准号: 10684863
• 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
• 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/10684863
• 关键词: Adolescent; Adult; Antibodies; Antibody Therapy; Biological Assay; Bone Injury; Bone Regeneration; CCR5 gene; Calvaria; Cartilage; Cell Differentiation process; Cell Transplantation; 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; Ligands; Maintenance; Mediating; Mesenchymal; Modeling; Molecular; Morphology; Mus; Mutation; Natural regeneration; Neural Crest; Osteoblasts; Osteogenesis; Osteogenesis Imperfecta; Osteoporosis; Patients; Periosteal Cell; Periosteum; Phenotype; Play; Population; Population Dynamics; Proliferating; Regulation; Reporting; Research Proposals; Role; Signal Transduction; Site; Skeletal bone; Source; Specific qualifier value; Specificity; Surgical sutures; TSC1 gene; Testing; Tissues; Transplantation; WNT Signaling Pathway; WNT1 gene; bone; bone healing; bone repair; 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 stem cell; skeletal tissue; stem cell biomarkers; stem cell function; stem cell migration; stem cell model; stem cell population; stem cells; tibia

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.

项目摘要 骨骼干细胞（SSC）对于骨和软骨的修复是必需的。在颅面 骨骼，骨膜骨骼干/祖细胞（P-SSC）和缝合缝隙间充质细胞在 骨稳态和再生。但是，由于分布限制和缺乏特定标记， 关于颅面P-SSC的功能及其在其特定调节机制中的功能知之甚少 稳态和对骨损伤的反应。成骨的患者（OI）患有失调的失调 颅面和骨骼骨稳态。 Wnt1突变引起隐性OI和早期发作 骨质疏松症和我们的初步数据支持改变颅面干细胞功能。因此，主要 该研究建议的目的是定义体内特征和独特的调节机制 颅面P-SSC，并测试Wnt1和α-螺旋杆菌素抗体的增强，Wnt信号的增强是 对于这些P-SSC对骨损伤的反应至关重要。我们假设颅面P-SSC具有独特的 与长骨P-SSC相比，分子特性，Wnt1对这些P-SSC的调节为 对于颅面骨稳态，再生和修复至关重要。结合先前已知的SSC 标记，我们对P-SSC有了新确定的选择性标记，使我们能够隔离高度纯化 小鼠P-SSC并分析其基因表达谱并通过 将这些P-SSC的移植到钙钙缺损中。因此，我们建议回答以下问题 实现特定目的：特定目标1：颅面p-的独特特征和功能是什么 SSC与长骨P-SSC相比。特定目标2：WNT1信号如何调节维护 和颅面P-SSC的功能？特定目标3：损失或增益的功能后果是什么 Wnt1和α-螺旋蛋白治疗颅骨再生？这些研究将确定因素 调节来自不同钙和长骨源的SSC的规格以及Wnt1的贡献 α-SOST处理在调节骨形成以及增殖，迁移和分化中的影响和影响 在稳态和修复中，神经rest衍生的刺激性与骨膜SSC。