Ontogenic Programming of Gingival Tissues and Risk of Periodontitis

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Title: Ontogenic Programming of Gingival Tissues and Risk of Periodontitis This proposal will focus on the use of a well-established nonhuman primate (Macaca mulatta) model of oral infection, inflammation, and disease and is a continuation of a long standing collaborative research relationship. Phenotype plasticity is a general attribute of genotypes, and it refers to the fact that the same set of genes can yield different phenotypic outcomes when exposed to distinct environmental conditions. This project will provide novel information on the oral immune system and changes that may occur early in the development of the oral mucosal immune armamentarium to the resident microbiome using a model of host- bacterial interactions at mucosal surfaces. The experimental design will address specific knowledge gaps about the acquisition and maturation of the oral microbiome in conjunction with the ontogeny of the immune system at a mucosal surface. The 2 paradigm shifting concepts in the proposal are: (1) the early acquired oral microbiome, generally transmitted maternally, will “program” the characteristics of gingival tissue responses in younger individuals and patterns of host transcriptome and microbiome will emerge defining an enhanced risk profile particularly related to an increased burden of putative oral pathogens; and (2) the early acquisition also alters immune/inflammatory response programming that will result in increased clinical features of periodontitis in an induced disease model even in younger individuals from periodontitis-susceptible families. The General Hypothesis is that “Development of specific immune response profiles, expressed in the oral mucosal tissues, is regulated by the characteristics of the early acquired microbiome,” and will be tested through 2 specific aims: Specific Aim 1: To delineate profiles of local immune gene expression in healthy gingival tissues derived from young nonhuman primates related to the acquired oral microbiome focusing on the Hypothesis: The immune response gene expression profiles in gingival tissues of young individuals will differ related to the characteristics of the early acquired oral microbiome. Specific Aim 2: To document the impact of early acquired oral microbiome-induced development and activation of mucosal immune responses on experimentally induced inflammation and periodontitis that will test the Hypothesis: Induction of progressing periodontitis will elicit a profile of immune response genes that hallmark the disease process, and these will differ related to the early acquired oral microbiome. There is sparse evidence of the dynamics of acquisition of commensal and pathogenic bacteria in the ecology interfacing with the intra-individual host responses in the development of the gingival immune response system. The scientific premise of this proposal is that variations in the early acquisition of the oral microbiome and programming of the mucosal immune responses are reflective of familial risk for periodontitis.