权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

PDGF-regulated stem cells and bone disease

PDGF调节的干细胞和骨疾病

基本信息

批准号：
10160786
负责人：
LORIN E OLSON
金额：
$ 37.3万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-12 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160786
关键词：
Address Adipocytes Adolescence Adult Beta Cell Biology Bone Diseases Bone Growth Bone Regeneration Cartilage Cell Differentiation process Cells Childhood Chondrocytes Collagen Coupling Data Defect Development Disease Equilibrium Exhibits Family Future Gene Deletion Goals Growth Health Human In Vitro Ligands Maintenance Maps Marrow Mediating Medicine Mesenchymal Minerals Molecular Mosaicism Mus Mutant Strains Mice Mutation Natural regeneration Oncogenic Osteoblasts Osteogenesis Osteoid Outcome PDGF Signaling Pathway PDGFRB gene Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphotransferases Platelet-Derived Growth Factor Platelet-Derived Growth Factor beta Receptor Process Production Publications Regenerative Medicine Reporting Role STAT protein STAT1 gene STAT1 protein STAT3 gene Signal Pathway Signal Transduction Skeleton Stat5 protein Stromal Cells Structure Syndrome Testing Transplantation Work adult stem cell base bone bone cell bone loss cartilage cell cell type combinatorial disease phenotype gain of function gain of function mutation genetic approach healing improved in vivo inhibitor/antagonist kinase inhibitor loss of function mutation molecular targeted therapies mouse genetics mouse model mutant new technology novel therapeutic intervention osteogenic osteoprogenitor cell postnatal prevent restoration skeletal skeletal disorder skeletal stem cell stem cell function stem cell growth stem cell proliferation stem cell self renewal stem cells treatment strategy

项目摘要

The growth and healing ability of the skeleton is possible because postnatal skeletal stem cells (SSCs) contin- ually generate bone-forming osteoblasts. Platelet-derived growth factor receptor β (PDGFRβ) is expressed on SSCs and osteoblasts, but its functional roles have not been characterized in vivo. Recently, humans with gain-of-function mutations in PDGFRB have been reported to exhibit skeletal disease involving progressive bone loss or skeletal overgrowth during childhood or adolescence. However, the target cell type and molecular mechanisms underlying PDGFRβ-driven skeletal disease are unknown. The applicant’s long-term goal is to develop a mechanistic understanding of how the PDGF pathway regulates mesenchymal cell plasticity. Bone forms because osteoblasts produce collagen-rich organic matrix called osteoid, which subsequently becomes mineralized into bone. Defects in cell plasticity and collagen production may underlie bone diseases driven by the PDGF pathway. Therefore, the specific objective in this proposal is to identify PDGF-regulated mecha- nisms controlling SSCs and their contribution to skeletal disease. The hypothesis underlying this project is that PDGFRβ regulates SSC proliferation and differentiation through the balance of downstream effectors of the signal transducer and activator of transcription (STAT) family. Aim 1 will use an SSC-targeted Cre/lox ap- proach to induce PDGFRβ activating mutations and combinatorial STAT deletions, and determine whether STATs mediate bone disease in vivo. Primary SSCs derived from mutant mouse bones will be used to investi- gate whether PDGFRβ-regulated STAT signaling regulates SSC self-renewal and differentiation in vitro or after transplantation. As an alternative approach, PDGFRβ activating mutations will be targeted to chondrocytes. Aim 2 will characterize new mouse models with the PDGFRβ activating mutations most commonly found in Penttinen syndrome and Kosaki overgrowth syndrome, V665A and P584R, respectively. Aim 2 will also ex- plore the benefits of kinase inhibitors for mice with gain-of-function PDGFRβ signaling. Aim 3 will study mice with gain- and loss-of-function mutations in PDGFRβ to identify the processes by which PDGFRβ regulates SSCs and their progeny during postnatal skeleton growth. Mutant cells will be fate mapped to determine how different levels of PDGFRβ activity regulate proliferation, differentiation, and cell fate in vivo. This work is ex- pected to define how the PDGFRβ signaling pathway mediates osteogenesis and how too much or too little signaling generates diseases of the skeleton, which will point to novel therapeutic strategies and better ap- proaches for bone repair. The results of these projects will significantly advance understanding of SSC regula- tory mechanisms. Information about signaling pathways and cell types that mediate disease-associated PDG- FRβ signaling will inform the development of new therapeutic approaches for skeletal diseases. And identifying the specific role of PDGFRβ in bone growth will begin to establish it as a molecular target for therapy. All of this information will improve the restoration of structure and function to diseased or damaged bones.

骨骼的生长和愈合能力是可能的，因为出生后骨骼干细胞（ssc）持续