Interferon Regulatory Factors and Periodontal Disease

干扰素调节因素与牙周病

• 批准号: 8190148
• 负责人: FRANK C GIBSON
• 金额: $ 25.35万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190148
• 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. PUBLIC HEALTH RELEVANCE: Type 1 Interferons, such as interferon-1, are key mediators of the immune response to pathogenic virus infection. Emerging data indicate that type 1 interferons are produced as part of the host response to bacterial infections; however, this area is exceedingly understudied in the context of periodontal disease. Based on our preliminary data we propose a focused set of studies to 1- define production of and 2- mechanism underlying host type 1 interferon production to the periodontal pathogen Porphyromonas gingivalis.

描述（由申请人提供）：由居住在口腔的细菌子集引起的炎症，例如牙龈毒性牙龈（PG）是牙周疾病（PD）的关键方面。人们认为这种慢性炎症会驱动严重疾病中的硬组织和软组织的破坏。出乎意料的是，已经在人类PD组织中检测到1型干扰素干扰素，干扰素（IFN）-1的水平升高，以及在激活正常T细胞（RANTES）时调节的干扰素诱导的蛋白质。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反应的一部分。这些干扰素在PD中的作用本质上是未知的。干扰素调节因子（IRF）是用于生产1型干扰素的主要转录因子。这些转录因子还调节其他已知参与炎症的基因的表达。 IRF3和IRF7信号已与宿主对牙周病原体的反应有关。但是，尚不清楚干扰素信号如何参与对牙周病原体的炎症的建立。我们的初步数据确定了用PG培养的野生型巨噬细胞的IFNB1基因的表达增加。此外，来自WT和IRF3-KO小鼠的巨噬细胞的活PG培养表现出IRF3在促炎性细胞因子和趋化因子产生中的部分作用。在这里，我们提出了一组详细的相关研究，以开始表征宿主对牙周病原体的宿主反应不足的领域，即IRF3信号传导的作用以及PG引起的炎症。这些研究将为将来扩大研究铺平道路，以定义慢性炎症和口腔骨骼流失的IRF3信号的确切机制，这是与PD相关的标志物。这项工作的最终目的是开始了解是否可以引入IRF3信号中的策略以增加当前的PD治疗方案。 公共卫生相关性：1型干扰素（例如干扰素1）是对致病病毒感染的免疫反应的关键介体。新兴数据表明，1型干扰素是作为对细菌感染的宿主反应的一部分而产生的。但是，在牙周疾病的背景下，该区域被极大地研究了。基于我们的初步数据，我们提出了一组重点的研究，以将1型宿主1型干扰素产生的生产和2-机理定义为牙周病原体卟啉单胞菌。