Effects of Aging on Macrophages and Bone Regeneration

衰老对巨噬细胞和骨再生的影响

基本信息

批准号：
8616534
负责人：
RALPH S MARCUCIO
金额：
$ 19.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616534
关键词：
Adolescent Affect Age Aging Alcohols Animal Model Animals Area Biology Bone Marrow Bone Marrow Transplantation Bone Regeneration CSF1 gene Calvaria Cell Aging Cell Communication Cells Chronic Clinical Elderly Excision Fracture Fracture Healing Goals Healed Health Hematopoietic Hormones Human Immune Immune system Immunosuppression Impaired wound healing Impairment In Vitro Incidence Individual Infiltration Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Lead Macrophage Activation Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Mesenchymal Stem Cells Modeling Morbidity - disease rate Mus Myeloid Cells Osteoblasts Osteogenesis Parathyroid gland Patients Pharmaceutical Preparations Phenotype Play Population Production Proteins Role Signal Transduction Site Therapeutic Work age effect age related aged aging population bone bone healing cell age cell type cytokine effective therapy healing immunosenescence improved juvenile animal macrophage mineralization mortality mouse model osteoblast differentiation receptor repaired stem cells therapeutic development triggering receptor expressed on myeloid cells 2 protein, human

项目摘要

DESCRIPTION (provided by applicant): Fragility fractures continue to cause significant morbidity and mortality in our aging population particularly because delayed healing and non-union during fracture healing is more common in the elderly. The ability to heal fractures decreases with age and effective therapies to enhance fracture healing are still needed. Aging also leads to significant changes in the immune system and the role of aging immune cells in the impairment of bone regeneration has not been examined. Our proposal will examine the hypothesis that age-related changes in myeloid cells promote dysfunctional bone regeneration during fracture repair in the elderly. We propose that while macrophages are beneficial to bone repair in young mice, in aged mice, the changes in macrophage phenotype and function lead to a detrimental effect of macrophages on bone regeneration. Our proposal focuses on determining how changes in macrophages with aging affect their functional interactions with osteoblasts and mesenchymal stem cells in bone regeneration. A long-term goal is the development of therapeutics directed at macrophages that will enhance fracture repair in geriatric patients. Our specific aims are: 1) Determine the effect of aging on osteal macrophages in the promotion of osteoblast differentiation and function. 2) Demonstrate the cell type(s) responsible for the "rescue" of fracture healing in older animals by bone marrow transplant from young animals. 3) Determine the effect of aging on macrophage and mesenchymal stem cell (MSC) interactions and determine the requirement for the myeloid cell receptor TREM2 in macrophage: MSC interactions

描述（由申请人提供）：脆弱性骨折继续引起我们衰老的人口的显着发病率和死亡率，尤其是因为骨折治愈过程中延迟的愈合和非工会在老年人中更为常见。仍然需要愈合裂缝的能力随着年龄的增长和有效疗法增强骨折愈合的能力而降低。衰老还会导致免疫系统发生重大变化，并且尚未研究衰老免疫细胞在骨骼再生损害中的作用。我们的建议将研究以下假设：老年人骨折修复过程中与年龄相关的髓样细胞的变化会促进功能失调的骨骼再生。我们建议，尽管巨噬细胞有益于年龄小鼠的年轻小鼠的骨骼修复，但巨噬细胞表型和功能的变化导致巨噬细胞对骨再生的有害影响。我们的建议着重于确定巨噬细胞的变化如何影响其与成骨细胞和间充质干细胞的功能相互作用。一个长期目标是开发针对巨噬细胞的治疗剂，可增强老年患者的断裂修复。我们的具体目的是：1）确定衰老对促进成骨细胞分化和功能的影响。 2）证明了由幼年动物的骨髓移植物在老年动物中“营救”骨折愈合的细胞类型。 3）确定衰老对巨噬细胞和间充质干细胞（MSC）相互作用的影响，并确定巨噬细胞中髓样细胞受体Trem2的需求：MSC相互作用