Interferon Regulatory Factors and Periodontal Disease

干扰素调节因素与牙周病

• 批准号: 8287188
• 负责人: FRANK C GIBSON
• 金额: $ 21.13万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287188
• 关键词: Address; Anaerobic Bacteria; Antigens; Area; Attention; Bacteria; Bacterial Infections; Biological Assay; Bone Marrow; Bone remodeling; Cells; Chronic; Clinical Data; Data; Disease; Future; Gene Expression; Genes; Genetic Transcription; Goals; Human; IRF3 gene; Immune response; Immunoglobulin G; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-6; Investigation; Knock-out; Knockout Mice; Knowledge; Life; Link; Measures; Mediating; Mediator of activation protein; Modeling; Mouth Diseases; Mus; Natural Immunity; Oral; Oral cavity; Pathway interactions; Periodontal Diseases; Porphyromonas gingivalis; Positioning Attribute; Production; Proteins; Relative (related person); Role; Severities; Signal Induction; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Tissues; Tooth Loss; Treatment Protocols; Tumor Necrosis Factor-alpha; Virus Diseases; Work; base; bone loss; chemokine; cytokine; defined contribution; human IRF3 protein; in vivo; interferon regulatory factor-3; macrophage; mouse model; novel; novel strategies; oral infection; pathogen; research study; response; soft tissue; transcription factor

DESCRIPTION (provided by applicant): Inflammation elicited by a subset of bacteria that inhabit the oral cavity such as Porphyromonas gingivalis (Pg) is a key facet of periodontal disease (PD). This chronic inflammation is thought to drive the destruction of both hard and soft tissues that in severe disease leads to tooth loss. Unexpectedly, elevated levels of the type 1 interferon, interferon (IFN)-1, as well as the interferon-induced protein Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) has been detected in human PD tissues. This is unexpected as type 1 interferons are part of the innate immune response to viral infection. The role of these interferons in PD is essentially unknown. Interferon regulatory factors (IRF) are the principal transcriptional factors used for production of type 1 interferons. These transcription factors also regulate expression of other groups of genes known to be involved in inflammation. IRF3 and IRF7 signaling have been implicated in host response to periodontal pathogens; however, it is unclear precisely how interferon signaling participates in the establishment of a nidus of inflammation to periodontal pathogens. Our preliminary data identify increased expression of the ifnb1 gene from wild type macrophages cultured with Pg. Furthermore, culture of live Pg with macrophages from WT and IRF3-KO mice demonstrate a partial role for IRF3 in pro-inflammatory cytokine and chemokine production. Here we propose a detailed set of related studies to begin to characterize a poorly understood area of host response to periodontal pathogens, namely the role of IRF3 signaling and with establishment of inflammation elicited by Pg. These studies will pave the way for future expanded investigations to define the precise mechanisms underlying IRF3 signaling in the context of chronic inflammation and oral bone loss, markers associated with PD. The ultimate goal of this work is to begin to understand whether strategies to intercede in IRF3-signaling can be channeled to augment current PD treatment regimens.

描述（由申请人提供）：由口腔中的细菌子集（如牙龈卟啉单胞菌（Pg））引起的炎症是牙周病（PD）的一个关键方面。这种慢性炎症被认为会导致硬组织和软组织的破坏，在严重的疾病中会导致牙齿脱落。出乎意料的是，在人PD组织中检测到1型干扰素、干扰素（IFN）-1以及干扰素诱导的正常T细胞表达和分泌的活化调节蛋白（RANTES）水平升高。这是出乎意料的，因为1型干扰素是对病毒感染的先天免疫应答的一部分。这些干扰素在PD中的作用基本上是未知的。干扰素调节因子（IRF）是用于产生1型干扰素的主要转录因子。这些转录因子还调节已知参与炎症的其他基因组的表达。IRF 3和IRF 7信号转导与宿主对牙周病原体的反应有关;然而，目前尚不清楚干扰素信号转导如何参与牙周病原体炎症病灶的建立。我们的初步数据表明，野生型巨噬细胞与Pg培养的ifnb 1基因表达增加。此外，野生型和IRF 3-KO小鼠的巨噬细胞与活Pg培养证明了IRF 3在促炎细胞因子和趋化因子产生中的部分作用。在这里，我们提出了一套详细的相关研究开始表征一个知之甚少的领域的主机响应牙周病原体，即IRF 3信号传导的作用，并建立炎症引起的PG。这些研究将铺平道路，为未来的扩大调查，以确定确切的机制IRF 3信号传导的背景下，慢性炎症和口腔骨丢失，标志物与PD。这项工作的最终目标是开始了解干预IRF 3信号传导的策略是否可以被引导以增强当前的PD治疗方案。