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.

项目总结