Investigation into the regulation and function of alkaline phosphatase (ALP) in host-microbe interactions.

摘要

This dissertation describes our investigation into the regulation and function of the innate immune modulator alkaline phosphatase (ALP). Animal intestine harbors a vast and complex microbial community, the gut microbiota. While resident microbes perform vital functions and confer tremendous benefits on their hosts, they also provide antigens and toxins that provoke host immune responses, which, if uncontrolled, could be detrimental to the host. Our lab previously demonstrated a negative feedback loop mediated by intestinal ALP (ALPI) which promotes immune tolerance to the commensal microbiota in zebrafish. We continue to investigate regulation mechanisms of ALP genes and explore their roles in modulating host-microbe interactions in various models. We have characterized four zebrafish alp genes, and we engineered tools for functional studies of these genes. Phylogenic analyses involving zebrafish alp genes revealed distinct evolution histories of animal ALP genes and implied their diversified functions. We then tested whether the regulation mechanism and the roles of zebrafish alpi were conserved in mice. We found the ALPI gene Akp3 was specifically upregulated by microbiota and played a role in immune education. We demonstrated the contribution of innate immune signaling to animal weight gain induced by high fat diet feeding. Finally, we discovered the positive correlation between neonatal ALPI activity and gestational age, suggesting potential therapeutic value of ALP supplementation for preventing necrotizing enterocolitis development in preterm infants.;This dissertation includes previously published and unpublished co-authored material.