Myeloid precursors and the microbiome in the osteoimmunology of aging

衰老骨免疫学中的骨髓前体和微生物组

• 批准号: 8876530
• 负责人: Julia F Charles
• 金额: $ 19.86万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876530
• 关键词: Address; Affect; Age; Age-Related Bone Loss; Aging; Animals; Arthritis; Bacteria; Biological Assay; Biology; Bone Marrow; Bone Resorption; Bone neoplasms; CD3 Antigens; Cell Culture Techniques; Cells; Cellular Immunity; Clinical; Collaborations; Data; Defect; Development; Disease; Elderly; Exhibits; Explosion; Fracture; Gene Expression; Germ-Free; Gnotobiotic; Grant; Health; Hematopoietic; Home environment; ITGAM gene; Immune; Immune response; Immune system; Immunity; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Arthritis; Knowledge; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Mediating; Metabolism; Minor; Modeling; Molecular Profiling; Mus; Myelogenous; Myeloid Cells; North Carolina; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; PTPRC gene; Population; Publications; Research Personnel; Resources; Risk; Rodent; Role; Signal Transduction; Skeletal system; Stromal Cells; Suppressor-Effector T-Lymphocytes; T cell response; T-Lymphocyte; TNFSF11 gene; Testing; Universities; age related; aged; bone; bone cell; bone loss; bone mass; bone quality; cell type; chemokine; clinically significant; cohort; cytokine; in vivo; innovation; insight; juvenile animal; microbiome; mouse model; research study; response; senescence; skeletal; skeletal abnormality; social implication; treatment strategy

DESCRIPTION (provided by applicant): Over the last decade, an intimate relationship between cells of the skeletal and immune systems has come under appreciation. This new field has been termed "osteoimmunology". A disturbance in the relationship between immune cells, bone forming osteoblasts (OB) and bone resorbing osteoclasts (OC) results in diseases such as osteoporosis, bone tumors and arthritis. Despite the common occurrence of these conditions in the elderly, osteoimmunology in aged animals has been understudied. As the worldwide population ages, these problems will become more common and the clinical and social implications created by this dearth of knowledge will grow in significance. This grant seeks to establish a better understanding of how aging affects osteoimmunology by leveraging recently developed models of OC biology and an exciting observation that germ-free (GF) mice are protected from age related osteoporosis. OCs differentiate from myeloid precursors under the influence of the cytokine RANKL, derived from osteocytes, activated T-cells or cytokine stimulated stromal cells. Overactive OCs underlie the skeletal abnormalities observed in osteoporosis, arthritis and bone malignancy. For years, the identity of the osteoclast precursor (OCP) was poorly defined. Recently, we showed that OCPs comprise a minor population of CD11blowLy6chigh myeloid cells. Interestingly, these OCPs exhibit a surprising second function: they are capable of potently suppressing T cell responses in vitro and in the setting of inflammatory arthritis in vivo. The first two aims of this grant evaluate the hypothesis that age related changes in CD11blowLy6chigh OCPs underpin two universal phenomena of aging: bone loss and reduced cellular immunity. The final aim comes on the heels of a recent explosion in our collective understanding of how the microbiome influences the immune system and metabolism to cause disease. However, relatively little is known about how the microbiota influences bone biology. In collaboration with Dr. Balfour Sartor at the National Gnotobiotic Rodent Resource Center at UNC we have generated preliminary data suggesting that the microbiome is a determinant of age-related osteoporosis. Aim 3 of this grant will determine how manipulation of the microbiome in aged mice changes bone mass and whether the microbiome from aged mice is capable of inducing osteoporosis in young animals. Strengths of this proposal include the significant problem it addresses (age related declines in bone quality and immunity), the diverse team of investigators with expertise in OC biology, immunology and the microbiome, the application of state of the art mouse models of osteoimmunology and innovative hypotheses regarding the effect of senescence on OCP biology and microbiome associated bone loss. These studies will further our understanding of how aging affects the intersection of bone biology and immunity, and may lead to new treatment strategies for osteoporosis, arthritis, cancer and infection.

描述（由申请人提供）：在过去的十年中，骨骼和免疫系统的细胞之间的密切关系受到重视。这一新领域被称为“骨免疫学”。免疫细胞、骨形成成骨细胞（OB）和骨再吸收破骨细胞（OC）之间的关系的紊乱导致诸如骨质疏松症、骨肿瘤和关节炎的疾病。尽管这些疾病在老年人中很常见，但老年动物的骨免疫学研究不足。随着全球人口老龄化，这些问题将变得更加普遍，这种知识的缺乏所造成的临床和社会影响将变得越来越重要。这项资助旨在通过利用最近开发的OC生物学模型和无菌（GF）小鼠免受年龄相关性骨质疏松症的令人兴奋的观察，更好地了解衰老如何影响骨免疫学。OC在细胞因子RANKL的影响下从骨髓前体分化，RANKL来源于骨细胞、活化的T细胞或细胞因子刺激的基质细胞。过度活跃的OC是骨质疏松症、关节炎和骨恶性肿瘤中观察到的骨骼异常的基础。多年来，破骨细胞前体（OCP）的身份定义不清。最近，我们发现，OCP包括一个少数群体的CD11blowLy6chigh骨髓细胞。有趣的是，这些OCP表现出令人惊讶的第二种功能：它们能够在体外和体内炎症性关节炎的情况下有效抑制T细胞反应。这项研究的前两个目的是评估与年龄相关的CD11blowLy6chigh OCPs变化是两种普遍的衰老现象的基础的假设：骨质流失和细胞免疫力下降。最终的目标是在我们对微生物组如何影响免疫系统和新陈代谢导致疾病的集体理解最近爆炸之后。然而，关于微生物群如何影响骨生物学的知识相对较少。在与美国国家非生物啮齿动物资源中心的Balfour Sartor博士合作下，我们已经产生了初步数据，表明微生物组是年龄相关性骨质疏松症的决定因素。这项资助的目标3将确定老年小鼠中微生物组的操纵如何改变骨量，以及老年小鼠的微生物组是否能够诱导年轻动物的骨质疏松症。该提案的优势包括它解决的重大问题（与年龄相关的骨质量和免疫力下降），具有OC生物学，免疫学和微生物组专业知识的多样化研究人员团队，最先进的骨免疫学小鼠模型的应用以及关于衰老对OCP生物学和微生物组相关骨丢失影响的创新假设。这些研究将进一步了解衰老如何影响骨生物学和免疫力的交叉，并可能导致骨质疏松症，关节炎，癌症和感染的新治疗策略。