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Epithelial Innate Immune Response to Oral Bacteria

上皮细胞对口腔细菌的先天免疫反应

基本信息

批准号：
7458100
负责人：
Whasun Oh Chung
金额：
$ 33.76万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7458100
关键词：
Abbreviations Address Bacteria Blocking Antibodies Body part CCR6 gene Cell Communication Cell Wall Collaborations Complex Condition Defensins Dendritic Cells Development Disease Ecology Endopeptidases Endothelial Cells Environment Epidermis Epithelial Epithelial Cells Epithelial Receptor Cell Exposure to Family Family member Feedback Fibroblasts Fusobacterium nucleatum G-Protein-Coupled Receptors Gene Activation Gene Expression Gene Silencing Genes Gingiva Goals Host Defense Human Immune Immune response Immune system Immunologic Monitoring Infection Inflammation Inflammatory Response Label Laboratories Lead Mediating Molecular Natural Immunity Nature Oral Oral health Oral mucous membrane structure Organism Pathogenesis Pattern Peptide Hydrolases Peptides Periodontal Diseases Periodontal Pocket Periodontium Phagocytosis Polymerase Chain Reaction Porphyromonas gingivalis Proteinase-Activated Receptors Readiness Receptor Activation Receptor Signaling Regulation Research Personnel Role Signal Pathway Signal Transduction Streptococcus gordonii Techniques Testing Toll-like receptors Virulence Factors Western Blotting Work acquired immunity antimicrobial peptide autocrine beta-Defensins beta-defensin-2 cell type chemokine commensal microbes cytokine in vivo microbial mutant natural antimicrobial neutrophil novel therapeutics oral bacteria oral cavity epithelium oral commensal pathogen pathogenic bacteria periodontopathogen periopathogen prevent programs receptor receptor function response sensor therapeutic target transcription factor

项目摘要

DESCRIPTION: This application will analyze the molecular mechanisms utilized by host gingival epithelial cells (GECs) in response to commensal and pathogenic oral bacteria, and the cellular receptors and signaling pathways associated with innate immunity in the periodontium. GECs respond to bacteria in an interactive manner secreting chemokines and cytokines to alert various cell types and attract neutrophils. They also produce natural antimicrobial peptides of the beta-defensin family. The defensin antimicrobial peptides are part of the innate immune system, a complex set of responses that keeps microbial invaders in check and maintains the microbial ecology of the healthy periodontal pocket. Human beta-defensin-2 (hBD-2) expression is upregulated in GECs in response to both commensal and pathogenic bacteria. In addition, this peptide is widely expressed in normal oral mucosa, in contrast to normal epidermis, suggesting that the innate immune responses of normal oral epithelia are at a heightened state of readiness. This application will test the hypotheses that commensal and pathogenic oral bacteria stimulate different networks of genes in gingival epithelial cells (GECs), that commensals prime the state of innate immunity of GECs for increased responsiveness to the environment and to subsequent exposure to pathogens, and that p-defensins are a major influence in this heightened innate immune response. These hypotheses build on evidence that commensal and pathogenic bacteria utilize different signaling pathways for regulation of hBD-2 gene expression and that hBD-2 itself influences innate immune responses and acts as a positive autocrine regulator. Finally, new evidence suggests involvement of the proteinase-activated receptor (PAR) family in innate immune and inflammatory responses. These receptors signal the presence of danger in the environment and contribute to inflammation. A final Aim will examine the function of these receptors to signal in response to Porphyromonas gingivalis, a major periodontopathogen that has proteinases as part of its set of virulence factors. These questions and hypotheses will be examined with the goal to better understand the global responses of GECs to commensal vs. pathogenic bacteria emphasizing gene expression programs and receptors that are critical for innate immune responses. This work will lay the groundwork for identifying new therapeutic targets to prevent and treat periodontal diseases.

描述：这项应用将分析宿主牙龈上皮细胞(GECs)响应共生和致病口腔细菌的分子机制，以及与牙周组织天然免疫相关的细胞受体和信号通路。GEC以一种相互作用的方式对细菌作出反应，分泌趋化因子和细胞因子来警告不同类型的细胞并吸引中性粒细胞。它们还产生β-防御素家族的天然抗菌肽。防御素抗菌肽是先天免疫系统的一部分，先天免疫系统是一组复杂的反应，可以阻止微生物入侵，并维持健康牙周袋的微生物生态。人类β-防御素-2(HBD-2)在GEC中的表达上调，对共生细菌和病原菌都有反应。此外，该多肽在正常口腔粘膜中广泛表达，与正常口腔黏膜相比，这表明正常口腔黏膜上皮的天然免疫反应处于高度准备状态。这一应用将检验这样的假设，即共生和致病口腔细菌刺激牙龈上皮细胞(GECs)中不同的基因网络，共生细菌启动GECs的天然免疫状态以提高对环境和随后接触病原体的反应，以及p-防御素是这种增强的先天性免疫反应的主要影响因素。这些假说建立在证据的基础上，即共生菌和病原菌利用不同的信号通路来调节HBD-2基因的表达，并且HBD-2本身影响先天免疫反应并发挥正向自分泌调节作用。最后，新的证据表明，蛋白酶激活受体(PAR)家族参与了先天免疫和炎症反应。这些受体发出环境中存在危险的信号，并导致炎症。最终目标将检查这些受体的功能，以响应牙龈卟啉单胞菌的信号，这是一种主要的牙周病原体，其毒力因子中含有蛋白酶。研究这些问题和假设的目的是更好地了解GEC对共生细菌和致病细菌的全球反应，重点是基因表达程序和受体，这些程序和受体对先天性免疫反应至关重要。这项工作将为寻找预防和治疗牙周病的新的治疗靶点奠定基础。