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: 9050600
• 负责人: Julia F Charles
• 金额: $ 20.48万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050600
• 关键词: Address; Affect; Age; Age-Related Bone Loss; Age-Related Osteoporosis; 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; gut microbiome; in vivo; innovation; insight; juvenile animal; microbiome; microbiota; mouse model; osteoimmunology; 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，骨骼和免疫系统细胞之间的紧密关系已受到赞赏。这个新领域被称为“骨气免疫学”。免疫细胞，骨形成成骨细胞（OB）和骨分辨骨细胞（OC）之间关系的干扰会导致骨质疏松症，骨肿瘤和关节炎等疾病。尽管这些疾病在老年人中发生了常见，但老年动物中的骨气免疫学已经研究了。随着全球人口的年龄，这些问题将变得越来越普遍，而缺乏知识所产生的临床和社会影响将变得重要。该赠款旨在通过利用最近开发的OC生物学模型来更好地了解衰老如何影响骨气免疫学，并且令人兴奋的观察结果，即无菌细菌（GF）小鼠受到与年龄相关的骨质疏松症的保护。 OC在细胞因子RANKL的影响下与髓样前体区分开，源自骨细胞，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）的身份定义很差。最近，我们表明OCP包含少数CD11Blowly6Chigh髓样细胞。有趣的是，这些OCP表现出令人惊讶的第二功能：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。该赠款的前两个目的评估了CD11Blowly6Chigh OCPS与年龄相关的变化的假设，其基础是两种衰老的普遍现象：骨质流失和降低的细胞免疫力。最终目的是在我们对微生物组如何影响免疫系统和代谢引起疾病的集体理解中的近期爆炸之后。但是，关于微生物群如何影响骨骼生物学的知之甚少。与UNC国家gnotobiotic Resource Center的Balfour Sartor博士合作，我们生成了初步数据，这表明微生物组是与年龄相关的骨质疏松症的决定因素。该赠款的目标3将决定老年小鼠对微生物组的操纵如何改变骨骼质量，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的研究人员，对OCP生物学对OCP生物学效果的骨质免疫学和创新假设的最先进的鼠标模型的应用以及对OCP生物学效果的应用。这些研究将进一步了解衰老如何影响骨骼生物学与免疫的交集，并可能导致针对骨质疏松，关节炎，癌症和感染的新治疗策略。