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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的共生菌群严格调节骨气免疫过程，介导骨后骨骼发展。我们的研究表明，共生肠道菌群抑制成骨细胞骨 - 形成细胞并增强破骨骨质骨质的细胞，从而损害骨质量。然而，辨别共生微生物群对整个寿命的骨骼影响的机制尚不清楚。骨气免疫学的研究表明，骨髓中的免疫球调节骨骼建模/重塑。尽管知道共生的肠道微生物群指导与宿主的串扰免疫，免疫机械研究阐明了共生肠道微生物群免疫调节对对骨骼成熟尚不清楚。研究者的博士后研究工作的初步发现建议共生的微生物群 - 主持人相互作用刺激完成信号传导，在系统中具有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于感染并调节免疫响应，突出显示完成在维持与共生微生物群保持体内平衡关系中的作用。我们的初步数据表明，共生微生物群上调循环完成过敏毒素C3a，也已在炎症性肠发病机理中暗示。补充接收器 C3AR在成骨细胞和破骨细胞上表达共生微生物群对健康和疾病成熟骨骼的影响。三个具体目标将解决在成骨细胞和破骨细胞中删除C3AR的转基因小鼠的临界体内和体外研究健康和硫酸钠（DSS）诱导的结肠炎。这三个目标将调查总体假设C3A的共生肠道菌群上调调节C3AR衍生的骨骼成熟整个生命周期中的健康和疾病。 AIM 1将阐明共生肠道微生物群在 C3AR介导的成骨细胞生成在正常和炎症下骨骼成熟和恶化排便状况。 AIM 2将检查对C3AR - 骨构成信号传导的共生肠道菌群作用健康与疾病的成熟和衰老骨骼。 AIM 3将确定益生菌是否给药调节聚会后骨骼发育过程中C3A/C3AR信号传导。阐明 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务成员的骨骼质量并防止骨骼确定衰老退伍军人。这项研究旨在定义将峰值骨质量准确性调节至承受与年龄有关的和/或与疾病有关的骨骼定义。这些研究将创新使用骨细胞特定的C3AR敲低模型，以确定微生物群的补体信号传导对骨骼成熟。值得注意的是，这项工作建议在峰值骨质量窗口期间进行益生菌干预为了定义共生微生物群在整个骨骼上的骨骼上的完成中的作用寿命。此外，该建议将在新的专业和职业领域提供扎实的职业发展申请人过渡到独立VA调查员所需的工具。这将完成通过提议的课程工作，动手培训，网络和心理经历，由CDA-提供 2机制。