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

人群牙龈炎症反应速率和水平差异的机制

• 批准号: 10596337
• 负责人: Richard Peters Darveau
• 金额: $ 63.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596337
• 关键词: 16S ribosomal RNA sequencing; Address; Adult; Bacteria; Cell Count; Clinical; Communities; Coupled; Custom; DNA; Data Set; Dental Plaque; Development; Disease; Educational workshop; Foundations; Gingiva; Gingival Crevicular Fluid; Gingivitis; Goals; Growth; Health; Homeostasis; Human; Immune; Immune response; Immunoassay; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Integration Host Factors; Intervention; Investigation; Knowledge; Measurement; Measures; Mediator; Metagenomics; Modeling; Multiomic Data; Participant; Pattern; Periodontic specialty; Periodontitis; Phase; Phenotype; Population; Predisposition; Preventive; Primary Prevention; Process; Public Health; RNA; Regulation; Research; Resistance; Resolution; Ribosomal DNA; Ribosomal RNA; Sampling; Testing; Therapeutic; Time; Tissues; Translating; Treatment Protocols; Variant; Work; chronic inflammatory disease; clinical phenotype; cytokine; design; host-microbe interactions; metabolomics; microbial; microbial community; microbiome; multiple omics; novel; oral microbiome; personalized medicine; preservation; resilience; response; subgingival microbiome; subgingival microbiota; success; treatment strategy

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.

摘要 这项研究的目的是提供一个路线图，以保持牙周健康的理解， 这些机制是人类群体中炎症反应变化的基础。最后， 这些信息将根据宿主的反应转化为个体化的预防和治疗方案 表型牙周炎是全世界成人中最流行的非传染性疾病之一， 重大公共卫生问题。根据最新的世界牙周病学研讨会， 在研究牙龈炎，一个先决条件可逆的疾病状态，作为一种手段，一级预防牙周炎。 健康的牙周组织与其伴随的口腔微生物组存在稳态关系。在大多数 这种关系导致宿主和微生物来源的免疫组分的组合， 产生一种活跃的炎症监视保护状态。这被称为健康的稳态。中断 这种健康的自我平衡状态发生在实验性和自然牙龈炎的发作期间， 牙龈的可逆性炎症在人类中诱导可逆的炎症状态的能力 为研究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 通过人类实验性牙龈炎（EG）模型。我们将利用我们以前的工作， 翻译人类实验牙龈炎模型，我们已经确定了三个不同的临床反应 表型，其表现与细菌驱动的炎症不同。我们将使用这些临床表型作为 这是探索人类炎症反应变异性的基础。具体来说，我们将确定 宿主成分和微生物生态演替模式对所观察到的 响应类型。这项研究的方法是确定细菌和宿主的过程， 使用先进的细菌和宿主并行多组学测量， 组分结合离体和体外机制研究，以确定宿主和相关微生物 决定宿主反应变化的功能。我们将采用全面的组合， 功能元组学并行（DNA和RNA 16 S测序，宏基因组学，代谢组学，定制 宿主介质组的多重免疫测定）沿着互补培养方法， 假设检验我们预计，我们建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-启用响应者类型 在不同研究中进行识别和进一步表征。从长远来看，这种基本的机械工作 通过在疾病起始期间鉴定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的发展，可以转化为个性化治疗， 干预策略。