Epithelial Cell Function in the Progression of Periodontal Disease

描述（由申请人提供）：牙周病是一类炎性疾病，如果不治疗，可导致软组织和硬组织破坏。虽然微生物是牙周病的病原体，但易感宿主的有害炎症反应可加重疾病。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起着多种作用 包括它们可以作为非造血先天免疫细胞（与传统的造血白细胞相反）发挥作用，其直接促进先天免疫并在粘膜稳态中起重要作用。先天免疫的过度激活或这种稳态的破坏可导致局部炎症的开始和/或恶化，如在牙周病中所见。因此，我们必须了解上皮细胞介导的免疫应答调节，以预防和/或治疗口腔粘膜炎症。TLR信号传导结果的动力学可归因于几个因素，包括TLR配体的类型、TLR配体的浓度、TLR配体刺激的持续时间和TLR配体参与的细胞类型。事实上，我们的初步数据表明，人和鼠口腔上皮细胞均以致耐受性方式对TLR 2刺激应答，而TLR 4刺激诱导促炎表型。在这里，我们提供了初步数据，其中在牙周病的多微生物模型中，口腔上皮细胞中MYD 88（一种关键TLR信号传导分子）的靶向诱导型敲除加剧了软组织浸润和骨丢失。我们认为口腔上皮细胞中MYD 88依赖性信号传导在控制炎症中起作用，从而限制局部炎症并避免牙周病。我们假设口腔上皮细胞MYD 88依赖性TLR信号传导引起致耐受性免疫调节，其抵消否则的炎症反应。在这里，我们将描绘免疫调节机制的口腔上皮细胞在牙周病的启动/进展。通过建立疾病进展的标志，我们将能够描绘新的干预措施可以应用于停止或逆转牙周病炎症的检查点。此外，将描绘TLR-受体的使用和信号传导事件，有助于调节与炎症上皮细胞表型，允许识别的目标，旨在减轻口腔上皮细胞相关炎症的新的干预措施。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。

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.