Epithelial Cell Function in the Progression of Periodontal Disease

上皮细胞在牙周病进展中的功能

基本信息

批准号：
8851566
负责人：
Shannon Margaret Wallet
金额：
$ 37.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851566
关键词：
Affect Anti-Inflammatory Agents Anti-inflammatory Attenuated Bone Resorption Cell physiology Cells Cytoprotection Data Defensins Disease Disease Progression Epithelial Cells Equilibrium Event Genes Growth Health Hematopoietic Homeostasis Human Immune Immune response Immunity Immunologic Receptors Infection Infiltration Inflammation Inflammatory Inflammatory Response Integration Host Factors Interferons Intervention Knock-out Knowledge Left Leukocytes Ligands Ligation Mediating Microbe Modeling Mononuclear Mus Natural Immunity Nature Oral Oral cavity Oral mucous membrane structure Organism Outcome Pathway interactions Peptides Periodontal Diseases Periodontitis Periodontium Phenotype Play Process Publishing Receptor Signaling Regulation Resolution Role Signal Pathway Signal Transduction Signaling Molecule Source Surface TLR2 gene TLR4 gene Tissues Toll-like receptors Triclosan antimicrobial bone loss cell type combat cytokine immune activation in vivo macrophage microbial microorganism novel oral cavity epithelium prevent receptor response soft tissue

项目摘要

DESCRIPTION (provided by applicant): Periodontal diseases are a class of inflammatory diseases which if left untreated can result in soft and hard tissue destruction. While microbes are etiological agents of periodontal disease, a harmful inflammatory response in a susceptible host can exacerbate disease. Oral epithelial cells are the first line of defense against microbial infection within the oral cavity. These important cells serve multiple roles at the mucosal surface including whereby they can function as non-hematopoietic innate immune cells (in contrast to traditional hematopoietic leukocytes) that contribute directly to innate immunity and play an important role in mucosal homeostasis. Over-activation of innate immunity or disruption of this homeostasis can result in initiation and/or exacerbation of localized inflammation as seen in periodontal diseases. Thus, it is imperative that we understand epithelial cell mediated regulation of immune responses to prevent and/or treat inflammation of oral mucosa. Dynamics of TLR signaling outcomes are attributable to several factors including the type of TLR ligand(s), concentration of TLR ligand(s), duration of stimulation by TLR ligand(s), and the cell type which is being engaged by TLR ligand(s). Indeed, our preliminary data demonstrates that both human and murine oral epithelial cells respond to TLR2 stimulation in a tolerogenic manner while TLR4 stimulation induces a pro- inflammatory phenotype. Here we present preliminary data whereby targeted, inducible knockout of MYD88 (a key TLR-signaling molecule) in oral epithelial cells exacerbated soft tissue infiltration and bone loss in a multi- microbial model of periodontal disease. We propose that MYD88-dependent signaling in oral epithelial cells plays a role in controlling inflammation thus limiting localized inflammation and averting periodontal disease. It is our hypothesis that oral epithelial cell MYD88-dependent TLR signaling causes tolerogenic immune tuning which counteracts otherwise inflammatory responses. Here we will delineate mechanisms of immune tuning by oral epithelial cells during periodontal disease initiation/progression. By establishing hallmarks of disease progression we will be able to delineate checkpoints at which novel interventions can be applied to halt or reverse periodontal disease inflammation. In addition, will delineate TLR-receptor usage and signaling events which contribute to regulatory versus inflammatory epithelial cell phenotypes, allowing for the identification of targets for novel interventions aimed at attenuating oral epithelial cell associaed inflammation. Finally, will determine in vivo efficacy of an anti- inflammatory agent in an oral epithelial cell dependent model of exacerbated periodontal disease and delineate the mechanism(s) of its regulation.

描述（由申请人提供）：牙周病是一类炎症性疾病，如果不及时治疗，会导致软组织和硬组织破坏。虽然微生物是牙周病的病因，但易感宿主体内有害的炎症反应可能会加剧疾病。口腔上皮细胞是口腔内抵抗微生物感染的第一道防线。这些重要的细胞在粘膜表面发挥多种作用包括它们可以作为非造血先天免疫细胞（与传统造血白细胞相反）发挥作用，直接促进先天免疫并在粘膜稳态中发挥重要作用。先天免疫的过度激活或这种稳态的破坏可能导致局部炎症的引发和/或加剧，如牙周病中所见。因此，我们必须了解上皮细胞介导的免疫反应调节，以预防和/或治疗口腔粘膜炎症。 TLR 信号传导结果的动态可归因于多种因素，包括 TLR 配体的类型、TLR 配体的浓度、TLR 配体刺激的持续时间以及 TLR 配体参与的细胞类型。 s）。事实上，我们的初步数据表明，人和小鼠口腔上皮细胞均以耐受性方式对 TLR2 刺激做出反应，而 TLR4 刺激则诱导促炎表型。在这里，我们提供了初步数据，在牙周病的多微生物模型中，口腔上皮细胞中 MYD88（一种关键的 TLR 信号分子）的靶向诱导敲除加剧了软组织浸润和骨质流失。我们认为口腔上皮细胞中的 MYD88 依赖性信号传导在控制炎症中发挥作用，从而限制局部炎症并避免牙周病。我们的假设是口腔上皮细胞 MYD88 依赖性 TLR 信号传导导致耐受性免疫调节，从而抵消其他炎症反应。在这里，我们将描述牙周病发生/进展期间口腔上皮细胞的免疫调节机制。通过建立疾病进展的标志，我们将能够划定检查点，在这些检查点上可以应用新的干预措施来阻止或逆转牙周病炎症。此外，还将描述 TLR 受体的使用和信号事件，这些事件有助于调节与炎症上皮细胞表型的比较，从而确定旨在减轻口腔上皮细胞相关炎症的新干预措施的靶点。最后，将确定抗炎剂在牙周病恶化的口腔上皮细胞依赖性模型中的体内功效，并描述其调节机制。