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.
Following birth infants are exposed to commensal (non-pathogenic) bacteria that colonize the gut, oral cavity, and other body surfaces exposed to the external environment. The proposed research will determine how specific commensal bacteria, prominent in the gut during post-natal development, impact bone formation in the growing skeleton. Understanding the influence of indigenous non-pathogenic bacteria on skeletal development will provide for potential clinical interventions, which could be applied to optimize bone formation, protecting against osteoporosis and periodontitis related skeletal deterioration.
| Steinkamp, H M; Hathaway-Schrader, J D; Chavez, M B et al. (2018) Tristetraprolin Is Required for Alveolar Bone Homeostasis. J Dent Res 97:946-953 |
| Novince, Chad M; Whittow, Carolyn R; Aartun, Johannes D et al. (2017) Commensal Gut Microbiota Immunomodulatory Actions in Bone Marrow and Liver have Catabolic Effects on Skeletal Homeostasis in Health. Sci Rep 7:5747 |
| Herbert, B A; Novince, C M; Kirkwood, K L (2016) Aggregatibacter actinomycetemcomitans, a potent immunoregulator of the periodontal host defense system and alveolar bone homeostasis. Mol Oral Microbiol 31:207-27 |
