Mechanisms underlying the variation in rate and levels of gingival inflammatory responses among the human population

摘要 这项研究的目标是提供一个路线图，以保持牙周健康通过了解 人类群体内炎症反应变化的基础机制。最终， 这些信息将根据宿主的反应被转化为个性化的预防和治疗方案 表型。牙周炎是全世界成年人中最常见的非传染性疾病之一， 主要的公共卫生问题。根据最新的牙周学世界研讨会，这是一个巨大的潜力 在研究牙周炎时，牙周炎是一种前驱的可逆性疾病状态，作为牙周炎的一级预防手段。 健康的牙周组织与其伴随的口腔微生物群存在着一种动态平衡的关系。在大多数 个体，这种关系导致宿主和微生物衍生的免疫成分的组合， 产生一种积极的炎症监视保护状态。这被称为健康的动态平衡。中断 这种健康的动态平衡状态发生在实验性和自然性牙周炎的发作期间，这是定义 是牙龈的可逆性炎症。在人类体内诱导可逆炎性状态的能力 为检验决定牙周健康和疾病的微生物-宿主相互作用提供了独特的基础 通过人实验性牙周炎(EG)模型。我们将利用我们之前的工作，与高度 翻译型人类实验性牙周炎模型，我们确定了三种不同的临床反应 表型，其行为与细菌驱动的炎症不同。我们将使用这些临床表型作为 为探索人类炎症反应的可变性奠定了基础。具体来说，我们将确定 寄主成分和微生物生态演替模式对观测到的变化的贡献 响应者类型。这项拟议研究的方法是确定细菌和宿主过程 使用先进的细菌和宿主的平行多组测量方法研究疾病的健康阶段 结合体外和体外机制研究确定宿主和相关微生物的成分 决定宿主反应变异的功能。我们将采用全面的组合 并行的功能元组学(DNA和RNA 16S测序、元基因组学、代谢组学、定制 宿主介体面板的多重免疫分析)以及互补的培养方法 假设检验。我们预计，我们提议的详细调查将立即带来好处 我们将生成并提供的综合多组学数据集的术语-支持响应者类型 有待通过研究确定并进一步确定其特征。从长远来看，这项基础性的机械性工作 通过在疾病起始和治疗过程中识别潜在的关键靶点，具有直接的临床和治疗价值 在每种不同的反应类型中发展，可以转化为个性化治疗和 干预策略。

Abstract The goal of this research is to provide a roadmap to maintain periodontal health by understanding the mechanisms which underlie the variation in inflammatory responses within the human population. Ultimately, this information will be translated to individualized preventive and treatment regimens based on host response phenotype. Periodontitis is one of the most prevalent non-communicable diseases in adults worldwide and a major public health concern. According to the latest World Workshop in Periodontics there is immense potential in studying gingivitis, an antecedent reversible disease state, as a means of primary prevention of periodontitis. Healthy periodontal tissue exists in a homeostatic relationship with its accompanying oral microbiome. In most individuals, this relationship results in a combination of host and microbial derived immune components that produce an active inflammatory surveillance protective state. This is termed healthy homeostasis. Disruptions of this healthy homeostatic state occur during episodes of both experimental and natural gingivitis, which is defined as reversible inflammation of the gingiva. The ability to induce a reversible inflammatory state in humans has provided a unique foundation to examine microbial-host interactions that dictate periodontal health and disease via the human Experimental Gingivitis (EG) model. We will capitalize on our previous work with the highly translational human experimental gingivitis model where we have identified three distinct clinical response phenotypes, which behave differently to bacterial-driven inflammation. We will use these clinical phenotypes as a foundation to explore the variability in the human inflammatory response. Specifically, we will determine the contributions of host components and microbial ecological succession patterns to the observed variations among responder types. The approach for this proposed research is to determine the bacterial and host processes in stages of health through disease using advanced parallel multi-omic measurements of both bacteria and host components coupled with ex vivo and in vitro mechanistic studies to determine the host and associated microbial functions that determine the variation in host responses. We will employ a comprehensive combination of functional meta-omics in parallel (DNA and RNA 16S sequencing, metagenomics, metabolomics, custom multiplex Immunoassay of host mediator panels) along with complementary cultivation approaches for hypothesis testing. We anticipate there will be an immediate benefit from our proposed detailed investigations in terms of the comprehensive multi-omic datasets we will generate and make available – enabling responder types to be identified and further characterized across studies. In the longer term, this fundamental mechanistic work has direct clinical and therapeutic value by identifying potential critical targets during disease initiation and development within each of the different response types that can translate to personalized treatment and intervention strategies.