Negative Regulation of Human Osteoclastogenesis
人类破骨细胞生成的负调控
基本信息
- 批准号:7555286
- 负责人:
- 金额:$ 43.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-08 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAutomobile DrivingBacteriaBone ResorptionBone remodelingCell LineageCell WallCellsChromatinChronicDefectDental PlaqueDevelopmentDiseaseDisease ProgressionEpigenetic ProcessEquilibriumFeedbackGenerationsGenetic TranscriptionHealedHumanImmuneInflammationInflammatoryInterleukin-10InvadedLipopolysaccharidesMediatingMediator of activation proteinMessenger RNAMicroRNAsModificationMolecularMorbidity - disease rateMusMutationMyelogenousNucleic AcidsOsteoclastsPathogenesisPathway interactionsPatientsPattern recognition receptorPeriodontal DiseasesPeriodontitisPhasePhysiologicalPorphyromonas gingivalisPost-Transcriptional RegulationProductionProteinsRateRegulationRelative (related person)ResolutionSignal TransductionSystemTLR4 geneTestingTherapeutic InterventionTimeTissuesToll-Like Receptor 2Tooth DiseasesTooth structurealveolar bonebasebonebone losscytokinehealinginflammatory bone resorptioninsightmicrobialnovel therapeuticsoral bacteriaoral biofilmosteoclastogenesispathogenic bacteriareceptorresponsesoft tissuespecies difference
项目摘要
DESCRIPTION (provided by applicant): Periodontitis is a chronic infectious/inflammatory disease in which bacteria present in oral biofilm/dental plaque drive an inflammatory state leading to dysregulated remodeling and destruction of periodontal soft tissues and alveolar bone. This application will focus on mechanisms of inhibition of the generation of osteoclasts during inflammatory bone resorption. Cell activation and inflammatory mediator production in response to pathogenic oral bacteria is mediated by `pattern recognition receptors' that recognize conserved microbial molecules. Among the most important pattern recognition receptors are Toll like receptors 2 (TLR2) and TLR4 that have been implicated in driving inflammatory bone resorption in periodontitis. At the same time as they activate inflammation, TLRs induce potent homeostatic mechanisms to limit the intensity of inflammation and thus limit associated tissue damage. The extent of inflammation and the rate of associated bone loss in periodontitis are determined by the balance between inflammatory factors and the relative potency of feedback and homeostatic mechanisms that oppose inflammation and bone resorption, and promote healing. Thus, disease progression is evidence of relatively ineffective feedback inhibition that is not able to restrain inflammation and bone resorption, in contrast to effective homeostatic regulation that occurs during physiological resolution of inflammation or during quiescent phases of disease. Our overarching hypothesis is that augmenting physiological homeostatic mechanisms represents an effective approach to limiting bone resorption associated with inflammation. Therefore, we have initiated studies to understand molecular mechanisms that restrain osteoclast formation in an inflammatory setting such as periodontal disease. We have found that IL-10, a prototypic negative regulator that is induced by TLRs and widely expressed in periodontitis, suppresses osteoclastogenesis by inhibiting signaling by RANK and TREM-2, key receptors important for osteoclastogenesis. In addition, we found that TLRs directly suppress the formation of osteoclast precursors by inhibiting RANK and TREM-2 expression during development of osteoclast precursors. Interestingly, our results revealed qualitative and quantitative differences between the regulation of human and murine osteoclastogenesis, including differential regulation of TREM-2, that may help explain species differences in regulation of bone remodeling. In this application, we will investigate inhibitory/homeostatic pathways and molecular mechanisms by which IL-10 and TLRs inhibit human osteoclastogenesis. We will use human systems that are directly relevant for periodontitis pathogenesis and may reveal mechanisms that are not readily apparent in murine systems. We anticipate that our studies will yield insights into homeostatic regulation that can be exploited for therapeutic interventions to suppress alveolar bone resorption associated with periodontitis. Project Narrative: Periodontitis is a dental disease in which oral bacteria cause inflammation that destroys teeth. In this application we will investigate mechanisms that inhibit osteoclasts, the cells that destroy tooth bone in periodontitis. We anticipate that our studies will yield insights that can be exploited for therapeutic interventions to suppress the bone and tooth destruction associated with periodontitis.
描述(由申请人提供):牙周炎是一种慢性感染性/炎症性疾病,口腔生物膜/牙菌斑中的细菌驱动炎症状态,导致牙周软组织和牙槽骨的重塑和破坏失调。本应用将侧重于炎性骨吸收过程中抑制破骨细胞生成的机制。在对口腔致病菌的反应中,细胞活化和炎症介质的产生是由“模式识别受体”介导的,该受体识别保守的微生物分子。其中最重要的模式识别受体是Toll样受体2 (TLR2)和TLR4,它们与牙周炎中驱动炎症性骨吸收有关。在激活炎症的同时,tlr诱导有效的体内平衡机制来限制炎症的强度,从而限制相关的组织损伤。牙周炎的炎症程度和相关骨质流失率取决于炎症因子与反馈和稳态机制的相对效力之间的平衡,这些机制反对炎症和骨吸收,并促进愈合。因此,疾病进展是相对无效的反馈抑制的证据,它不能抑制炎症和骨吸收,与炎症生理消退或疾病静止期发生的有效稳态调节相反。我们的首要假设是,增强生理稳态机制是限制与炎症相关的骨吸收的有效方法。因此,我们已经开始了研究,以了解在炎症环境中抑制破骨细胞形成的分子机制,如牙周病。我们发现IL-10是一种由tlr诱导并在牙周炎中广泛表达的典型负调节因子,它通过抑制RANK和TREM-2的信号传导来抑制破骨细胞的形成,而RANK和TREM-2是破骨细胞形成的关键受体。此外,我们发现tlr通过抑制破骨细胞前体发育过程中RANK和TREM-2的表达直接抑制破骨细胞前体的形成。有趣的是,我们的研究结果揭示了人类和小鼠破骨细胞发生调节的定性和定量差异,包括TREM-2的差异调节,这可能有助于解释骨重塑调节的物种差异。在这项应用中,我们将研究IL-10和TLRs抑制人类破骨细胞发生的抑制/稳态途径和分子机制。我们将使用与牙周炎发病机制直接相关的人类系统,并可能揭示在小鼠系统中不易明显的机制。我们预计我们的研究将产生对体内平衡调节的见解,可以用于抑制与牙周炎相关的牙槽骨吸收的治疗干预。项目简介:牙周炎是一种由口腔细菌引起的炎症破坏牙齿的牙齿疾病。在这个应用程序中,我们将研究抑制破骨细胞的机制,在牙周炎中破坏牙骨的细胞。我们预计我们的研究将产生可以用于治疗干预的见解,以抑制与牙周炎相关的骨和牙齿破坏。
项目成果
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Lionel B Ivashkiv其他文献
Lionel B Ivashkiv的其他文献
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