Impact of the Microbiome on Osteoimmunology and Skeletal Development

 描述（由申请方提供）：婴儿暴露于肠道（非致病性）细菌，这些细菌自然定植于肠道、口腔和暴露于外部环境的其他体表。出生后肠道细菌的定植调节免疫系统的发育，对健康与疾病具有终身影响。有趣的是，最近的基因组研究表征了构成正常肠道植物群的不同细菌，并确定了不同的共生细菌，这些细菌在生长和发育过程中有效刺激特定的T淋巴细胞免疫细胞群。虽然广泛的研究集中在肠道植物群在保护免受病原性细菌和自身免疫性疾病的背景下的免疫调节作用，但肠道植物群对正常发育过程的影响在很大程度上是未知的。骨免疫学的研究（免疫细胞与骨细胞的相互作用）表明，骨髓中特异性T淋巴细胞免疫细胞调节骨的建模和重塑。尽管知道肠道植物群指导出生后早期发育中T淋巴细胞介导的免疫力的发育，但尚无已知的已发表研究阐明肠道植物群对儿科骨骼发育的免疫调节作用。研究者的博士后研究工作中发表的发现表明，植物植物群与宿主免疫系统的相互作用诱导低水平的炎症状态，其在发育中的骨骼中具有分解代谢作用。在发育中的GF vs. SPF小鼠模型中，研究肠道植物群对骨髓CD 4 +/CD 8 + T细胞造血和骨建模的免疫调节作用的拟定原始研究与促进对调节骨骼健康的正常发育过程的理解高度相关。三个具体目标将优化基于使用无菌小鼠与无特定病原体小鼠构建的强有力的体外和体内策略，以研究骨骼植物群调节骨环境中的效应CD 4 +/CD 8 + T细胞的总体假设，在骨骼发育期间对骨建模具有分解代谢作用。第一个具体目标将调查正常微生物群对成骨细胞生成的影响;第二个具体目标将确定破骨细胞生成潜力是否被骨骼植物群改变;第三个具体目标将阐明介导骨骼植物群分解代谢对骨骼发育影响的机制。这项研究定义了骨骼发育的骨骼植物群免疫调节作用，这与促进对骨免疫过程调节达到峰值骨量的理解高度相关，对骨质疏松症和牙周炎相关的骨骼退化具有影响。重要的是，这些研究将提供强大的职业发展和科学经验，支持候选人向科学独立的过渡。

 DESCRIPTION (provided by applicant): Infants are exposed to commensal (non-pathogenic) bacteria that naturally colonize the gut, oral cavity, and other body surfaces exposed to the external environment. Post-natal colonization of the gut by commensal bacteria regulates the development of the immune system, having lifelong implications for health vs. disease. Of interest, recent genomic studies characterizing the diverse bacteria making up the normal gut flora, have identified distinct commensal bacteria which potently stimulate specific T-lymphocyte immune cell populations during growth & development. While extensive research has focused on the commensal gut flora immuno- regulatory effects in the context of protection against pathogenic bacteria and autoimmune diseases, the commensal flora impact on normal developmental processes is largely unknown. The study of osteoimmunology (*immune cell interactions with bone cells) has shown that specific T- lymphocyte immune cells in the bone marrow regulate bone modeling and remodeling. Despite knowledge that the commensal gut flora directs the development of T-lymphocyte mediated immunity in early post-natal development, there are no known published studies elucidating the commensal gut flora immuno-regulatory effects on pediatric skeletal development. Published findings from the investigator's postdoctoral research work, suggest that commensal flora interactions with the host immune system induce a low level inflammatory state which has catabolic effects in the developing skeleton. The proposed original research investigating the commensal gut flora's immuno-modulatory effects on marrow CD4+/CD8+ T-cell hematopoiesis and bone modeling in the developing GF vs. SPF mouse model is highly relevant in advancing the understanding of normal developmental processes regulating skeletal health. Three specific aims will optimize strong in vitro and in vivo strategies built upon the use of germ-free vs specific- pathogen-free mice to investigate the overall hypothesis that the commensal flora regulates effector CD4+/CD8+ t-cells in the bone environment, having catabolic effects on bone modeling during skeletal development. The first specific aim will investigate the influence of the normal microbiota on osteoblastogenesis; the second specific aim will determine if the osteoclastogenic potential is altered by the commensal flora; the third specific aim will elucidate mechanisms mediating the commensal flora's catabolic effects on skeletal development. This research defining the commensal flora immunomodulatory effects on skeletal development is highly relevant in advancing the understanding of osteoimmunological processes regulating the attainment of peak bone mass, having implications for osteoporosis and periodontitis related skeletal deterioration. Importantly, these studies will provide a strong career development & scientific experience supporting the candidate's transition to scientific independence.