Role of Complement in Commensal Microbiota Actions Regulating Sketal Maturation

补体在调节骨骼成熟的共生微生物群作用中的作用

• 批准号: 10656406
• 负责人: Jessica Diann Hathaway-Schrader
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656406
• 关键词: Adult; Age; Aging; Anaphylatoxins; Animals; Area; Bone Density; Bone Marrow; Bone Resorption; C3AR1 gene; Cells; Complement; Complement 3a; Complement Receptor; Data; Deterioration; Development; Disease; Funding Mechanisms; Germ-Free; Goals; Gonadal Steroid Hormones; Growth; Health; Immune; Immune response; Immune signaling; Immunity; Immunologic Stimulation; Impairment; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Intervention; Intestines; Knowledge; Lactobacillus plantarum; Longevity; Mediating; Mediator; Mentors; Modeling; Mus; Osteoblasts; Osteoclasts; Osteopenia; Osteoporosis; Pathogenesis; Phase; Probiotics; Process; Reporting; Research; Research Personnel; Resources; Risk; Role; Services; Signal Transduction; Skeletal Development; Skeleton; Solid; System; Testing; Therapeutic Intervention; Training; Transgenic Mice; Up-Regulation; Veterans; Work; age related; aged; bone; bone cell; bone fracture repair; bone health; bone loss; bone mass; career; career development; commensal microbes; deprivation; dextran sulfate sodium induced colitis; experience; fracture risk; germ free condition; gut microbiota; host microbiota; immunoregulation; improved; in vivo; innovation; knock-down; microbiota; osteoclastogenesis; osteoimmunology; pathogenic microbe; postdoctoral investigator; receptor; recruit; service member; skeletal; skeletal maturation; substantia spongiosa; tool; young adult

Abstract Commensal microbiota critically regulates osteoimmune processes mediating post-pubertal skeletal development. Our studies have shown that the commensal gut microbiota suppresses osteoblastic bone- forming cells and enhances osteoclastic bone-resorbing cells, which impairs bone mass accrual. However, mechanisms discerning commensal microbiota effects on bone across the lifespan are unclear. The study of osteoimmunology has shown that immune cells in the bone marrow regulate bone modeling/remodeling. Despite knowledge that the commensal gut microbiota directs crosstalk with host immunity, immune mechanistic studies elucidating the commensal gut microbiota immunomodulatory effects on skeletal maturation are unclear. Preliminary findings from the investigator’s postdoctoral research work suggest that commensal microbiota-host interactions stimulate complement signaling to have system catabolic effects in the maturing skeleton in health and disease. Complement signaling protects the host from infection and modulates the immune response, highlighting the role of complement in maintaining a homeostatic relationship with the commensal microbiota. Our preliminary data demonstrated that the commensal microbiota upregulates circulating complement anaphylatoxin C3a, which has also been implicated in inflammatory bowel pathogenesis. Complement receptor C3aR is expressed on both osteoblasts and osteoclasts, implying that C3a may be a critical regulator of commensal microbiota effects on the maturing skeleton in health and disease. Three specific aims will address critical in vivo and in vitro studies utilizing transgenic mice deleting C3aR in both osteoblasts and osteoclasts in health and under dextran sodium sulfate (DSS)-induced colitis. These three aims will investigate the overall hypothesis that the commensal gut microbiota upregulation of C3a regulates C3aR derived skeletal maturation in health and disease throughout the lifespan. Aim 1 will elucidate the role of commensal gut microbiota on C3aR-mediated osteoblastogenesis in skeletal maturation and deterioration under normal and inflammatory bowel conditions. Aim 2 will examine commensal gut microbiota actions on C3aR-osteoclastogenic signaling in the maturing and aging skeleton in health and disease. Aim 3 will determine whether probiotic administration regulates C3a/C3aR signaling during post-pubertal skeletal development. Elucidating the relationship between C3/C3aR signaling, the gut microbiota, and bone will provide opportunities for therapeutic interventions to optimize bone mass accrual in young service members and protect against skeletal deterioration in aging Veterans. This research seeks to define osteoimmunological processes regulating peak bone mass accrual to withstand either age-related and/or disease-related skeletal deterioration. These studies will innovatively use bone cells specific C3aR knockdown models to determine microbiota derived complement signaling effects on skeletal maturation. Notably, this work proposes probiotic interventions during a peak bone mass accrual window to define the role of the commensal microbiota on complement C3a/C3aR on the skeleton throughout the lifespan. Additionally, this proposal will provide solid career development in new areas of expertise and career tools necessary for the applicant's transition to an independent VA investigator. This will be accomplished through proposed coursework, hands-on training, networking, and mentoring experiences provided by the CDA- 2 mechanism.

抽象的 共生微生物群严格调节介导青春期后骨骼的骨免疫过程 发展。我们的研究表明，共生肠道微生物群抑制成骨细胞骨- 形成细胞并增强破骨细胞骨吸收细胞，从而损害骨量增长。然而， 共生微生物群在整个生命周期对骨骼影响的机制尚不清楚。 骨免疫学研究表明，骨髓中的免疫细胞调节骨 建模/改造。尽管知道共生肠道微生物群引导与宿主的串扰 免疫，免疫机制研究阐明共生肠道微生物群的免疫调节作用 骨骼成熟情况尚不清楚。研究人员博士后研究工作的初步结果表明 共生微生物群-宿主相互作用刺激补体信号传导以产生系统分解代谢效应 健康和疾病中成熟的骨骼。 补体信号传导可保护宿主免受感染并调节免疫反应，强调 补体在维持与共生微生物群稳态关系中的作用。我们的 初步数据表明，共生微生物群上调循环补体 过敏毒素 C3a，也与炎症性肠病发病机制有关。补体受体 C3aR 在成骨细胞和破骨细胞上都有表达，这意味着 C3a 可能是成骨细胞和破骨细胞的关键调节因子。 共生微生物群对健康和疾病中成熟骨骼的影响。将解决三个具体目标 利用在成骨细胞和破骨细胞中删除 C3aR 的转基因小鼠进行关键的体内和体外研究 健康和右旋糖酐硫酸钠（DSS）引起的结肠炎。这三个目标将调查总体 假设共生肠道微生物群 C3a 的上调调节 C3aR 衍生的骨骼成熟 整个生命周期的健康和疾病。目标 1 将阐明共生肠道微生物群对 C3aR介导的成骨细胞生成在正常和炎症条件下骨骼成熟和退化中的作用 肠道状况。目标 2 将检查共生肠道微生物群对 C3aR 破骨细胞信号传导的作用 健康和疾病中骨骼的成熟和老化。目标 3 将确定是否施用益生菌 在青春期后骨骼发育过程中调节 C3a/C3aR 信号传导。阐明之间的关系 C3/C3aR 信号传导、肠道微生物群和骨骼将为治疗干预提供机会 优化年轻服役人员的骨量增长并防止骨骼老化 退伍军人。 本研究旨在定义调节峰值骨量累积的骨免疫过程 承受与年龄相关和/或与疾病相关的骨骼退化。这些研究将创新地​​利用 骨细胞特异性 C3aR 敲低模型，用于确定微生物群衍生的补体信号传导效应 骨骼成熟。值得注意的是，这项工作提出了在骨量累积峰值窗口期间进行益生菌干预 确定共生微生物群对整个骨骼中补体 C3a/C3aR 的作用 寿命。此外，该提案将为新的专业知识和职业领域提供坚实的职业发展 申请人过渡为独立 VA 调查员所需的工具。这将实现 通过 CDA 提供的拟议课程、实践培训、网络和指导经验 2机制。