Rejuvenating fracture repair: The role of the macrophage and Beta-catenin

恢复骨折修复：巨噬细胞和 β-连环蛋白的作用

• 批准号: 9026036
• 负责人: Benjamin Aaron Alman
• 金额: $ 37.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026036
• 关键词: Address; Adolescent; Affect; Age; Aging; Alleles; Animal Model; Animals; Automobile Driving; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Bone Regeneration; Cell Count; Cells; Characteristics; Clinical; Conditioned Culture Media; Data; Data Science; Development; Dose; Down-Regulation; Elderly; Extracellular Matrix Proteins; Fracture; Fracture Healing; Genes; Healed; Hematopoietic; In Vitro; Individual; Injury; Knowledge; LDL-Receptor Related Protein 1; Label; Liquid Chromatography; Mass Spectrum Analysis; Mechanics; Mesenchymal; Morbidity - disease rate; Mus; Nefopam; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Parabiosis; Patient Care; Patients; Phase; Phenotype; Physiologic pulse; Plasminogen Activator Inhibitor 1; Process; Property; Proteins; Regimen; Rejuvenation; Role; Series; Site; Tankyrase; Testing; Therapeutic; Translating; Undifferentiated; Up-Regulation; Vascular blood supply; Work; aged; base; beta catenin; bone; cell type; defined contribution; enhancing factor; healing; high throughput screening; improved; in vivo; inhibitor/antagonist; juvenile animal; macrophage; mortality; novel; older patient; osteoblast differentiation; osteogenic; pre-clinical; prevent; public health relevance; repaired; research study; response; tandem mass spectrometry; treatment duration; two-dimensional

 DESCRIPTION (provided by applicant): The rate of bone repair slows with aging, and little is known about the mechanisms responsible for this delayed repair process. The slow healing is responsible for increased morbidity and even mortality when older adults sustain a fracture. During fracture repair, undifferentiated mesenchymal cells accumulate and differentiate to osteoblasts to reestablish the mechanical properties of bone. We discovered that β-catenin needs to be precisely regulated for normal fracture repair, and both up and down regulation inhibit the ability of cells to become osteoblasts. β-catenin protein level was substantially increased during fracture repair with aging, and this was associated with an inhibition of undifferentiated cells to become osteoblasts. Furthermore, we found that hematopoetic cells from young mice could suppress β-catenin and rejuvenate repair. Here we will use heterochronic parabiosis experiments, in which young and old mice share a blood supply, and bone marrow transplantation experiments to identify the cell type responsible for the rejuvenation effect. Furthermore, we will study the role of secreted factors produced by young hematopoetic cells, that we identified using mass spectroscopy, in bone repair in aging using genetically modified mice. This work will identify novel potential therapies to improve fracture repair in aging, ultimately reducing the morbidity associated with injury in older individuals.

 描述（由申请人提供）：骨修复的速度随着年龄的增长而减慢，并且对这种延迟修复过程的机制知之甚少。当老年人持续骨折时，缓慢的愈合是增加发病率甚至死亡率的原因。在骨折修复过程中，未分化的间充质细胞聚集并分化为成骨细胞以重建骨的机械性能。我们发现β-catenin需要被精确调控以实现正常的骨折修复，而上调和下调都会抑制细胞成为成骨细胞的能力。β-catenin蛋白水平在骨折修复过程中随着年龄的增长而显著增加，这与未分化细胞成为成骨细胞的抑制有关。此外，我们发现来自年轻小鼠的造血细胞可以抑制β-连环蛋白并使修复恢复活力。在这里，我们将使用异时共生实验（其中年轻和年老的小鼠共享血液供应）和骨髓移植实验来识别负责复兴效应的细胞类型。此外，我们将研究分泌的年轻造血细胞产生的因子的作用，我们确定使用质谱，在骨修复老化使用转基因小鼠。这项工作将确定新的潜在疗法，以改善老年人骨折修复，最终降低老年人受伤相关的发病率。