Ontogenic Programming of Gingival Tissues and Risk of Periodontitis

牙龈组织的个体编程和牙周炎的风险

• 批准号: 10214993
• 负责人: Jeffrey L Ebersole
• 金额: $ 62.76万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214993
• 关键词: 5 year old; Address; Adolescent; Affect; Animals; Bacterial Infections; Characteristics; Chronic; Clinical; Cross-Sectional Studies; Data; Development; Disease; Disease model; Ecology; Enrollment; Environment; Excision; Experimental Designs; Exposure to; Expression Profiling; Family; Future; Gene Expression; Genes; Genotype; Gingiva; Growth; Health; Heritability; Homeostasis; Human; Immune; Immune Response Genes; Immune response; Immune system; Immunity; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Knowledge; Life; Ligature; Link; Literature; Longitudinal prospective study; Macaca mulatta; Modeling; Monitor; Mothers; Mucosal Immune Responses; Mucous Membrane; Natural Immunity; Newborn Infant; Oral; Oral cavity; Oral mucous membrane structure; Outcome; Pathogenicity; Pattern; Periodontitis; Phenotype; Predisposition; Process; Publishing; Reporting; Research; Resistance; Resolution; Risk; Sampling; Site; Surface; System; Testing; Tissues; Variant; base; collaborative approach; commensal bacteria; gut microbiome; innovation; juvenile animal; microbial; microbiome; microorganism; mucosal site; multidisciplinary; nonhuman primate; novel; oral infection; oral microbial community; oral microbiome; oral pathogen; pathogenic bacteria; periodontopathogen; programs; response; transcriptome; translational model; young mother

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.

标题：牙龈组织的个体编程和牙周炎的风险 该提案将重点关注使用成熟的非人类灵长类动物（猕猴）口腔模型 感染、炎症和疾病，是长期合作研究的延续 表型可塑性是基因型的一般属性，是指同一集合的事实。 当暴露于不同的环境条件时，基因可以产生不同的表型结果。 项目将提供有关口腔免疫系统和早期可能发生的变化的新信息 使用宿主模型开发针对常驻微生物组的口腔粘膜免疫武器 粘膜表面的细菌相互作用。实验设计将解决特定的知识差距。 关于口腔微生物组的获得和成熟与免疫个体发育的结合 该提案中的两个范式转变概念是： (1)早期获得的口腔微生物组，通常是母体传播的，会“编程”这些特征 年轻个体的牙龈组织反应以及宿主转录组和微生物组的模式将 出现了一种增强的风险状况，特别是与假定的口腔病原体负担增加有关； 和 (2) 早期获得也会改变免疫/炎症反应程序，从而导致 在诱发疾病模型中，牙周炎的临床特征有所增加，甚至在年轻个体中也是如此 牙周炎易感家庭。 一般假设是“特定免疫反应谱的发展，以口腔表达 粘膜组织，受到早期获得的微生物组特征的调节，”并将进行测试 通过 2 个具体目标： 具体目标 1：描绘健康人群局部免疫基因表达谱 来自年轻非人类灵长类动物的牙龈组织与获得的口腔微生物组相关，重点关注 假设：年轻人牙龈组织中的免疫反应基因表达谱将 不同之处与早期获得的口腔微生物组的特征有关。 具体目标 2：记录 早期获得性口腔微生物组诱导的粘膜免疫反应的发育和激活的影响 关于实验诱导的炎症和牙周炎，将检验假设：诱导进展 牙周炎会引发一系列免疫反应基因，这些基因标志着疾病过程 与早期获得的口腔微生物组有关的差异很少有证据表明获得的动态。 生态中的共生菌和病原菌与个体内宿主反应的相互作用 牙龈免疫反应系统的发展 该提议的科学前提是： 口腔微生物组早期获取和粘膜免疫反应编程的变化 反映了牙周炎的家族风险。