Impact of the Microbiome on Osteoimmunology and Skeletal Development

 描述(由申请人提供)：婴儿暴露在共生(非致病)细菌中，这些细菌自然定植于肠道、口腔和其他暴露于外部环境的身体表面。出生后肠道共生细菌的定植调节免疫系统的发展，对健康和疾病具有终生影响。有趣的是，最近的基因组研究表征了组成正常肠道菌群的各种细菌，发现了不同的共生细菌，它们在生长和发育过程中能够有效地刺激特定的T淋巴细胞免疫细胞群。虽然广泛的研究集中在共生肠道菌群在预防病原菌和自身免疫性疾病方面的免疫调节作用，但共生菌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(*免疫细胞与骨细胞的相互作用)的研究表明，骨髓中特定的T淋巴细胞免疫细胞调节骨骼的建模和重塑。尽管已知共生肠道菌群在出生后早期指导T淋巴细胞介导的免疫发育，但尚无已知的已发表的研究阐明共生肠道菌群对儿童骨骼发育的免疫调节作用。这位研究人员的博士后研究成果表明，与宿主免疫系统的共生菌群相互作用会诱导一种低水平的炎症状态，这对发育中的骨骼具有分解代谢的作用。在发育中的GF和SPF小鼠模型中，研究共生肠道菌群对骨髓CD4+/CD8+T细胞造血和骨骼建模的免疫调节作用的原创性研究对于促进对调节骨骼健康的正常发育过程的理解具有重要意义。三个特定的目标将优化建立在无菌小鼠和无特定病原体小鼠基础上的强大的体外和体内策略，以调查共生菌群调节骨骼环境中的效应细胞CD4+/CD8+T细胞的总体假设，在骨骼发育过程中对骨骼建模具有分解代谢作用。第一个特定目的是研究正常微生物区系对成骨细胞生成的影响；第二个特定目的是确定共生菌群是否改变了破骨细胞的生成能力；第三个特定目的是阐明共生菌群对骨骼发育的分解代谢作用的机制。这项研究明确了共生菌群对骨骼发育的免疫调节作用，对于促进对调节达到峰值骨量的骨免疫学过程的理解具有重要意义，对骨质疏松症和牙周炎相关的骨骼退化具有重要意义。重要的是，这些研究将提供强有力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.