Role of sulfide in oral microbiota-host interactions that promote periodontitis

硫化物在促进牙周炎的口腔微生物群与宿主相互作用中的作用

基本信息

批准号：
10788640
负责人：
Apollo Stacy
金额：
$ 24.9万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10788640
关键词：
Abscess Actinobacillus actinomycetemcomitans Adult Aerobic Aerobic Bacteria Affect Alveolar Bone Loss Anaerobic Bacteria Antibodies Biological Assay Bismuth Cell Respiration Communities Complement Core Facility Cysteine Data Detection Development Development Plans Disease Educational workshop Environment Etiology Flow Cytometry Formulation Future Gases Genetic Goals Grant Growth Human Hydrogen Sulfide Immune response Immune system Immunity Immunologics Immunology In Vitro Individual Inflammatory Innovative Therapy Interleukin-6 Interleukins Intramural Research Program Knowledge Laboratories Ligature Link Literature Mediating Mentors Modeling Mus National Institute of Dental and Craniofacial Research Oral Oral Microbiology Oxidants Pathology Periodontal Diseases Periodontitis Persons Pharmaceutical Preparations Positioning Attribute Production Productivity Proliferating Research Research Personnel Research Project Grants Resistance Resources Respiration Risk Role Sulfides Supervision T-Lymphocyte Testing Therapeutic Thigh structure Tissues Tooth Loss Tooth structure Training United States National Institutes of Health Writing alveolar bone antimicrobial bacterial genetics bone loss career career development co-infection cytokine dysbiosis fitness global health host microbiota human disease immunopathology in vivo insight microbial microbiome mouse model mutant neutrophil novel oral immunology oral microbial community oral pathogen pathogen response skills targeted treatment translational therapeutics

项目摘要

Project Summary/Abstract Research: Periodontitis (gum disease) is one of the most common inflammatory diseases worldwide, affecting nearly 50% of adults (65 million people) in the US alone. Untreated, it can destroy the tissues that support the teeth, eventually resulting in tooth loss. The cause of periodontitis is linked to the outgrowth of multiple, rather than individual, pathogens in the oral microbiota. For instance, co-detection of Aggregatibacter actinomycetemcomitans (Aa) with Filifactor alocis is a much greater predictor of future tissue destruction than detection of Aa alone. However, how Aa and F. alocis interact to elicit pathology while evading host immunity remains poorly understood. Microbiota-host interactions are often mediated by microbial metabolites, and a major metabolite of F. alocis is hydrogen sulfide, a toxic gas highly enriched in periodontitis. Based on my preliminary data, I hypothesize that F. alocis-derived sulfide triggers an immunological cascade that drives tissue destruction while constructing a niche for Aa to proliferate via sulfide-resistant anaerobic respiration. Of note, inexpensive, non-toxic drugs already exist that selectively inhibit anaerobic respiration (tungstate) or sequester sulfide (bismuth). To test my hypothesis and the therapeutic value of these drugs, I will dissect how F. alocis- derived sulfide impacts Aa (Aim 1) and the oral immune system (Aim 2) in complementary mouse models: thigh abscess, which allows for precise control over composition of the infecting community, and ligature-induced periodontitis, which allows for the assessment of oral immune responses. Through these Aims, I will potentially establish innovative therapies targeted against microbiota-host interactions that promote periodontal disease. Career Goals: My overarching goal as an independent investigator is to integrate the fields of oral microbiology and immunology as a strategy to gain novel insight into the etiology of periodontitis. To achieve this goal, I require additional training and knowledge in oral immunology as well as professional development in skills essential for leading a successful laboratory. Career Development Plan and Environment: My mentor Y. Belkaid, a renowned expert in microbiota-host interactions, is an investigator in the NIH Intramural Research Program, one of the largest research centers in the world. In this unique environment, I will directly benefit from the numerous resources in place to support my research project and career development, including microbiome and immunology core facilities, frequent seminars and opportunities to engage colleagues/mentors, and regular workshops on grant-writing, mentoring, and laboratory management. Furthermore, I have assembled a mentoring team who will complement my expertise in Aa and the abscess model by closely overseeing my training in the ligature model (NIDCR-based co-mentor N. Moutsopoulos) and F. alocis (collaborators R. Lamont and H. Fletcher) as well as my transition to independence. By the end of my training plan, I will be well-positioned to launch a productive independent career at the intersection of oral microbiology and immunology.

项目概要/摘要研究：牙周炎（牙龈疾病）是世界范围内最常见的炎症性疾病之一，仅在美国就影响了近 50% 的成年人（6500 万人）。未经治疗，它会破坏组织支撑牙齿，最终导致牙齿脱落。牙周炎的病因与牙周组织的生长有关口腔微生物群中存在多种而不是单一的病原体。例如，联合检测聚集菌与 Filifactor alocis 结合的放线菌 (Aa) 是未来组织破坏的更好预测因子单独检测Aa。然而，Aa 和 F. alocis 如何相互作用来引发病理，同时逃避宿主免疫仍然知之甚少。微生物群与宿主的相互作用通常是由微生物代谢物介导的， F. alocis 的主要代谢物是硫化氢，这是一种在牙周炎中高度富集的有毒气体。根据我的根据初步数据，我假设 F. alocis 衍生的硫化物触发了驱动组织的免疫级联反应破坏，同时构建 Aa 通过抗硫化物无氧呼吸增殖的生态位。值得注意的是，已经存在廉价、无毒的药物，可以选择性抑制无氧呼吸（钨酸盐）或隔离硫化物（铋）。为了检验我的假设和这些药物的治疗价值，我将剖析 F. alocis- 衍生硫化物影响互补小鼠模型中的 Aa（目标 1）和口腔免疫系统（目标 2）：大腿脓肿，可以精确控制感染群落的组成，以及结扎诱导的牙周炎，可以评估口腔免疫反应。通过这些目标，我将有可能建立针对促进牙周病的微生物群与宿主相互作用的创新疗法。职业目标：作为一名独立研究者，我的首要目标是整合口腔领域微生物学和免疫学作为获得牙周炎病因学新见解的策略。为了实现这一目标为了实现目标，我需要口腔免疫学方面的额外培训和知识以及技能方面的专业发展对于领导一个成功的实验室至关重要。职业发展规划和环境：我的导师Y. Belkaid 是微生物群与宿主相互作用方面的著名专家，也是 NIH 校内研究的研究员计划，世界上最大的研究中心之一。在这个独特的环境中，我将直接受益支持我的研究项目和职业发展的大量资源，包括微生物组和免疫学核心设施、频繁的研讨会和与同事/导师接触的机会，以及定期关于拨款写作、指导和实验室管理的研讨会。此外，我还组装了一个指导团队将通过密切监督我在 Aa 和脓肿模型方面的专业知识来补充我的专业知识结扎模型培训（基于 NIDCR 的合作导师 N. Moutsopoulos）和 F. alocis（合作者 R. Lamont）和 H. Fletcher）以及我向独立的过渡。在我的培训计划结束时，我将处于有利位置在口腔微生物学和免疫学的交叉领域开展富有成效的独立职业生涯。