Epithelial Cell Function in the Progression of Periodontal Disease

上皮细胞在牙周病进展中的功能

• 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
• 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

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）：牙周疾病是一类炎症性疾病，如果未治疗，可能会导致软组织破坏。尽管微生物是牙周疾病的病因学药，但易感宿主的有害炎症反应会加剧疾病。口腔上皮细胞是针对口腔内微生物感染的第一道防线。这些重要细胞在粘膜表面发挥多种作用 包括它们可以用作非杂型先天性免疫细胞（与传统造血白细胞相比），这些细胞直接有助于先天免疫，并在粘膜稳态中起重要作用。过度激活先天免疫力或这种体内平衡的破坏可能导致牙周疾病中所见的局部炎症的启动和/或加剧。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/或治疗口服粘膜的炎症。 TLR信号传导结果的动力学归因于多种因素，包括TLR配体的类型，TLR配体的浓度，TLR配体刺激持续时间以及TLR配体参与的细胞类型。确实，我们的初步数据表明，人和鼠口腔上皮细胞都以耐受性方式对TLR2刺激反应，而TLR4刺激诱导了促炎性表型。在这里，我们提供了初步数据，在该数据中，在牙周疾病多微生物模型中，口腔上皮细胞中的MyD88（密钥TLR信号分子）的诱导型敲除（一种关键的TLR信号分子）加剧了软组织浸润和骨质流失。我们建议口腔上皮细胞中的MyD88依赖性信号传导在控制炎症中起作用，从而限制了局部炎症和避免牙周疾病。我们的假设是，口服上皮细胞MyD88依赖性TLR信号传导会导致耐受性免疫调节，从而抵消了其他炎症反应。在这里，我们将在牙周疾病开始/进展过程中描述口腔上皮细胞免疫调节的机制。通过建立疾病进展的标志，我们将能够描绘出可以将新干预措施应用于停止或反向牙周疾病炎症的检查站。此外，还将描绘有助于调节性和炎症性上皮细胞表型的TLR受体使用和信号传导事件，从而鉴定出旨在衰减口腔上皮细胞相关炎症的新型干预措施的靶标。最后，将确定抗炎症剂在口腔上皮细胞依赖性模型中的体内功效，并描述其调节的机制。