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Regulation of Skeletal progenitor cells in Osteogenesis Imperfecta

成骨不全中骨骼祖细胞的调节

基本信息

批准号：
10528208
负责人：
Brendan Lee
金额：
$ 66.24万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-13 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10528208
关键词：
Affect Animal Model Biological Bone Diseases Bone Injury Bone Marrow Bone Regeneration Breathing CCR5 gene Cell Count Cell Proliferation Cell model Cell physiology Cells Characteristics Clinical Clinical Trials Collagen Craniofacial Abnormalities Defect Deformity Disease Environment Extracellular Matrix Face Fracture Gene Expression Profile Genetic Diseases Goals Heterogeneity Human Impaired healing Injury KDR gene Label Ligands Location Maintenance Mastication Methods Modeling Modification Molecular Mus Mutation Natural regeneration Oral Osteoblasts Osteogenesis Imperfecta Patients Periosteal Cell Periosteum Population Procollagen RANTES Regulation Reporter Series Severities Signal Transduction Site Source Surface Tail Technology Testing Transforming Growth Factor beta Transplantation Vascular Endothelial Growth Factors Wild Type Mouse Work base bone bone healing bone repair bone strength cell motility clinically relevant combinatorial cortical bone craniofacial craniofacial bone craniofacial disorder fracture risk improved in vivo insight intravital imaging long bone migration mouse model neutralizing antibody novel osteoprogenitor cell postnatal progenitor receptor restoration selective expression single cell analysis single-cell RNA sequencing skeletal skeletal disorder skeletal stem cell stem stem cell function stem cells success

项目摘要

PROJECT SUMMARY Osteogenesis Imperfecta (OI) is a congenital bone and oral-facial disorder that mainly affects bone with less well characterized alterations in bone healing and repair. Like other skeletal diseases, at least some of the progressive bone and craniofacial defects in OI patients have been attributed to changes in the populations and functions of their stem/progenitor cells. In general, stem cells require a specialized environment for their maintenance and function. Nevertheless, how normal or defective structural components of collagen regulate skeletal stem/progenitor cells (SSPCs) is essentially unknown. Therefore, the goal of this proposal is to define the in vivo characteristics and function of skeletal stem/progenitor cells in OI and to understand how an abnormal OI extracellular matrix alters these stem/progenitor cells in the context of bone regeneration and repair. We previously showed that the Mx1Cre and αSMAGFP combination can selectively label skeletal stem cells in the periosteum and that these Mx1ÈαSMAGFPÈ periosteal cells are long-term repopulating stem cell subsets responsible for lifelong regeneration of periosteal osteoblasts and bone repair. Moreover, our preliminary study revealed that these periosteal SSPCs are Prx1GFP positive and selectively express KDR (VEGFR2). Human primary periosteal cells also express KDR with multi-lineage differentiation potentials. Notably, we found that these KDRÈ periosteal progenitor cells are significantly decreased in OI bones. Hence, we hypothesize that the abnormal OI matrix deregulates the number and function of periosteal and bone marrow SSPCs and the OI- associated molecular changes in stem/progenitor cells are critical for the progressive deformity and delayed or defective healing of bones. By using a series of OI animal models and SSPC reporter mice, in which we can differentially label periosteal and bone marrow SSPC subsets, in combination with intravital imaging and the latest single-cell RNA-sequencing technology, we plan to pursue the following specific aims. In aim 1, we will define the in vivo characteristics and function of periosteal and bone marrow SSPCs in clinically relevant OI mouse models. In aim 2, we will define key OI matrix factors that regulate SSPC function and improve both craniofacial and long bone healing. Upon completion of this work, we will achieve new biological insights into a better understanding of the molecular and cellular mechanisms that differentially regulate SSPCs under OI pathophysiological conditions.

项目总结