In vitro models of subgingival communities and their in vivo pathogenic potential

龈下群落的体外模型及其体内致病潜力

• 批准号: 8857319
• 负责人: Patricia Diaz
• 金额: $ 11.38万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857319
• 关键词: Affect; Animal Model; Bacteria; Behavior; Biological Preservation; Biomass; Bioreactors; Characteristics; Communities; Complex; Dependency; Development; Disease; Ecology; Environment; Etiology; Event; Forsythia; Functional disorder; Growth; Health; High-Throughput Nucleotide Sequencing; Human; Immune; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Knowledge; Lead; Mediating; Metabolic; Modeling; Monitor; Mucins; Mus; Nature; Nutritional; Oral; Oral cavity; Oxidative Stress; Oxygen; Pathogenesis; Pathogenicity; Periodontal Pocket; Periodontitis; Periodontium; Population; Porphyromonas gingivalis; Prevalence; Preventive; Process; Relative (related person); Research; Ribosomal RNA; Role; Serum; Source; Structure; Taxon; Testing; Therapeutic; Time; Tissues; Treponema denticola; Weight; base; bone loss; improved; in vitro Model; in vivo; member; microbial; microbial community; microbiome; microorganism; named group; novel; novel strategies; pathogen; pressure; prevent; pyrosequencing

DESCRIPTION (provided by applicant): Periodontitis is an inflammatory condition of the supporting tooth structures that results from the interaction of pathogenic subgingival communities with the host. The pathophysiology of this condition is not completely understood and thus the development of novel preventive or therapeutic strategies remains elusive. Microbial communities are complex dynamic entities in which microorganisms interact with each other, therefore displaying different phenotypic characteristics than individual species. Moreover, a community context modifies the pathogenic potential of microorganisms, which is realized not only by their direct interaction with host tissues but also indirectly by modulating te behavior of the whole community. Therefore, understanding the etiology of periodontitis requires considering microbial communities as the infectious challenge rather than focusing on single species as causative agents. Community models that approximate the taxonomic complexity, environmental conditions and growth rate of microorganisms in the subgingival environment are not available. Such models are necessary to investigate the inter-species interactions that support pathogenic communities. Moreover, animal models of periodontitis are required in which the pathogenic potential of human-like communities could be investigated. In this proposal, we will use recently acquired knowledge on the microbiome composition of humans with periodontitis to develop a 20-species model subgingival community. This model will be developed under continuous culture in nutritional and environmental conditions similar to those in vivo. Using this community model we will investigate inter-species interactions important for the survival of periodontitis-associated species. In particular, we will test the role of a group called "subgingival core species" which are important components of communities in health and disease and potentially serve as community metabolic anchors by supporting periodontitis-associated taxa. We will then evaluate the colonization and pathogenicity of the model 20-species community in the murine oral cavity, testing the hypothesis that microorganisms growing as a community and pre-adapted to environmental pressures such as oxygen are better able to colonize and induce periodontitis than single species. Accordingly, the specific aims of this proposal are: 1) To develop and characterize a chemostat-based subgingival community model representative of periodontitis and test the role of core species as fundamental for the survival of periodontitis- associated community members and 2) To develop a community-based oral gavage murine model of periodontitis. The models proposed will have great impact in the field as they will allow research on the pathogenesis of periodontitis to move beyond the study of single species, thereby facilitating identification of key events that modulate the establishmen of pathogenic communities and their effects on host tissues. This knowledge is likely to direct the development of new strategies for preservation of periodontal health.

描述（由申请人提供）：牙周炎是由致病性龈下群落与宿主相互作用引起的支持牙齿结构的炎症性疾病。这种情况的病理生理学尚未完全了解，因此新的预防或治疗策略的开发仍然难以捉摸。微生物群落是复杂的动态实体，微生物在其中相互作用，因此表现出与单个物种不同的表型特征。此外，群落环境改变了微生物的致病潜力，这不仅是通过微生物与宿主组织的直接相互作用来实现的，而且还通过调节整个群落的行为来间接实现。因此，了解牙周炎的病因需要将微生物群落视为感染挑战，而不是关注单一物种作为病原体。目前还没有能够估计龈下环境中微生物的分类复杂性、环境条件和生长速率的群落模型。这些模型对于研究支持致病菌群落的物种间相互作用是必要的。此外，需要牙周炎动物模型来研究类人群落的致病潜力。在本提案中，我们将利用最近获得的有关牙周炎人类微生物组组成的知识来开发 20 种龈下群落模型。该模型将在类似于体内的营养和环境条件下连续培养下开发。使用这个群落模型，我们将研究对牙周炎相关物种的生存至关重要的物种间相互作用。特别是，我们将测试一个称为“龈下核心物种”的群体的作用，该群体是健康和疾病群落的重要组成部分，并可能通过支持牙周炎相关分类群而充当群落代谢锚。然后，我们将评估 20 种模型群落在小鼠口腔中的定植和致病性，检验这样的假设：作为一个群落生长并预先适应氧气等环境压力的微生物比单一物种更能够定植并诱发牙周炎。因此，本提案的具体目标是：1）开发和表征代表牙周炎的基于恒化器的龈下群落模型，并测试核心物种作为牙周炎相关群落成员生存的基础的作用；2）开发基于群落的口腔强饲小鼠牙周炎模型。所提出的模型将在该领域产生巨大影响，因为它们将使牙周炎发病机制的研究超越单一物种的研究，从而有助于识别调节致病菌群落建立及其对宿主组织影响的关键事件。这些知识可能会指导制定保护牙周健康的新策略。