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：
8738567
负责人：
RALPH S MARCUCIO
金额：
$ 19.75万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738567
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 Stem cells 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 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）：脆性骨折继续在老龄化人口中造成显着的发病率和死亡率，特别是因为骨折愈合过程中延迟愈合和不愈合在老年人中更为常见。骨折愈合的能力随着年龄的增长而降低，仍然需要有效的治疗来增强骨折愈合。衰老还会导致免疫系统发生显着变化，而衰老的免疫细胞在骨再生受损中的作用尚未得到研究。我们的提案将检验以下假设：骨髓细胞中与年龄相关的变化会促进老年人骨折修复过程中功能失调的骨再生。我们认为，虽然巨噬细胞有利于年轻小鼠的骨修复，但在老年小鼠中，巨噬细胞表型和功能的变化导致巨噬细胞对骨再生产生不利影响。我们的建议重点是确定巨噬细胞随衰老的变化如何影响其与成骨细胞和间充质干细胞在骨再生中的功能相互作用。长期目标是开发针对巨噬细胞的疗法，以增强老年患者的骨折修复。我们的具体目标是：1）确定衰老对骨巨噬细胞在促进成骨细胞分化和功能方面的影响。 2) 展示通过年轻动物的骨髓移植来“拯救”老年动物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，并确定巨噬细胞中骨髓细胞受体TREM2的需求：MSC相互作用