Inflammatory responses initiated by periodontal bacterial DNA

由牙周细菌 DNA 引发的炎症反应

• 批准号: 8508624
• 负责人: Sinem Esra Sahingur
• 金额: $ 11.43万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508624
• 关键词: AIM2 gene; Adverse effects; Agonist; Animal Model; Arterial Fatty Streak; Bacterial DNA; Biological; Cell Line; Cells; Clinical; DNA; DNA receptor; Data; Disease; Distant; Environment; Escherichia coli; Fusobacterium nucleatum; Future; Genetic Polymorphism; Gingiva; Health; Human; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferons; Invaded; Knowledge; Laboratories; Lead; Ligands; Microbial Biofilms; Molecular; Mus; Myeloid Cells; Nucleic Acids; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Periodontal Diseases; Periodontal Infection; Periodontitis; Play; Porphyromonas gingivalis; Predisposition; Production; Receptor Signaling; Reporting; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Site; Small Interfering RNA; Stream; Structure; Synovial Fluid; Systemic disease; TLR2 gene; TLR4 gene; TLR9 gene; Time; Tissues; Western Blotting; cytokine; design; extracellular; in vivo; interest; macrophage; mouse toll-like receptor 9; pathogen; promoter; public health relevance; receptor; receptor expression

DESCRIPTION (provided by applicant): The host immune system responds to invading pathogens by detecting pathogen-associated molecular patterns (PAMPs) through an array of receptors called pattern recognition receptors (PRRs). The role of extracellular PRRs and their ligands are very well characterized in the pathogenesis of periodontal disease. Bacterial nucleic acids represent a group of PAMPs that are mainly recognized through intracellular PRRs, including Toll like receptor 9, AIM2 (absent in melanoma-2) for inflammasome and DAI. Recent data regarding the contribution of DNA and intracellular DNA receptors has changed our view of disease pathogenesis in a variety of conditions. This may be true for periodontal infections and in fact, studies conducted in our laboratory also support this hypothesis. Our preliminary studies identified increased expression of TLR9, AIM2 and DAI in periodontally diseased tissues compared to healthy sites. Furthermore, we also reported differential expression of a single nucleotide polymorphism (SNP) in the TLR9 promoter in periodontally-diseased versus -healthy subjects. Moreover, we also showed that periodontal bDNA-initiated inflammatory pathways are operant both in myeloid and non-myeloid cells of importance for periodontal pathology. Periodontal disease is not only limited to gingival tissues but also is associated with various systemic diseases. Identification of periodontal bDNA in distant sites suggests that bDNA-initiated inflammatory pathways may not be only important in periodontal pathology but also contribute to periodontal disease adverse effects on systemic health. Hence, it is important to determine the biological mechanisms involved in periodontal bDNA-initiated signaling pathways and their interactions with other PAMPs and PRRs to understand their importance in the pathogenesis of periodontitis and systemic diseases. We believe, cumulative effect of DNA in the tissues may either directly promotes a hyper-inflammatory state and/or interferes with other PAMPs and signaling pathways modifying the immune responses. This proposal is designed to extend our previous studies to primary human and mouse macrophages determine the role of periodontal bDNA and its receptors with regard to induction of cytokines, tolerance/cross and synergy.

描述（由申请人提供）：宿主免疫系统通过一系列称为模式识别受体（PRR）的受体检测病原体相关分子模式（PAMP），从而对入侵病原体做出反应。细胞外PRR及其配体在牙周病发病机制中的作用非常清楚。细菌核酸代表一组主要通过细胞内PRR识别的PAMP，包括Toll样受体9、炎性小体的AIM 2（在黑素瘤-2中不存在）和DAI。关于DNA和细胞内DNA受体的贡献的最新数据改变了我们对各种条件下疾病发病机制的看法。这可能是真的牙周感染，事实上，在我们的实验室进行的研究也支持这一假设。我们的初步研究发现，与健康部位相比，牙周病组织中TLR 9，AIM 2和DAI的表达增加。此外，我们还报道了牙周病患者与健康受试者中TLR 9启动子单核苷酸多态性（SNP）的差异表达。此外，我们还发现，牙周bDNA启动的炎症途径是操作性的髓细胞和非髓细胞的牙周病理学的重要性。牙周病不仅限于牙龈组织，而且还与各种全身性疾病有关。牙周bDNA在遥远的网站的鉴定表明，bDNA启动的炎症途径可能不仅是重要的牙周病理，但也有助于牙周病对全身健康的不良影响。因此，重要的是要确定参与牙周bDNA启动的信号转导通路及其与其他PAMPs和PRRs的相互作用的生物学机制，以了解其在牙周炎和全身性疾病的发病机制的重要性。我们相信，组织中DNA的累积效应可能直接促进高度炎症状态和/或干扰其他PAMP和改变免疫反应的信号通路。该建议旨在将我们先前的研究扩展到原代人类和小鼠巨噬细胞，以确定牙周bDNA及其受体在诱导细胞因子、耐受性/交叉和协同作用方面的作用。