Epithelial Innate Immune Response to Oral Bacteria

产品说明：该应用程序将分析宿主牙龈上皮细胞（GECs）响应于牙周和致病性口腔细菌的分子机制，以及与牙周组织中先天免疫相关的细胞受体和信号通路。GEC以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以警告各种细胞类型并吸引中性粒细胞。它们还产生β-防御素家族的天然抗微生物肽。防御素抗菌肽是先天免疫系统的一部分，这是一组复杂的反应，可以控制微生物入侵者并维持健康牙周袋的微生物生态。人β-防御素-2（hBD-2）表达在GECs中响应于细菌和病原菌两者而上调。此外，与正常表皮相反，该肽在正常口腔粘膜中广泛表达，表明正常口腔上皮的先天免疫应答处于高度的准备状态。该应用程序将测试的假设，牙龈和致病性口腔细菌刺激牙龈上皮细胞（GECs）中的基因的不同网络，牙龈素总理GECs的先天免疫的状态，以增加对环境的反应，并随后暴露于病原体，和p-防御素是在这种提高先天免疫反应的主要影响。这些假说建立在以下证据的基础上：大肠杆菌和致病菌利用不同的信号传导途径来调节hBD-2基因表达，hBD-2本身影响先天免疫应答，并充当正自分泌调节剂。最后，新的证据表明蛋白酶激活受体（PAR）家族参与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。最后一个目标将检查这些受体的功能，以响应牙龈卟啉单胞菌，一个主要的牙周病病原体，具有蛋白酶作为其毒力因子的一部分的信号。这些问题和假设将进行检查，目的是更好地了解GECs对真菌与病原菌的全球反应，强调基因表达程序和受体对先天免疫反应至关重要。这项工作将奠定基础，确定新的治疗目标，以预防和治疗牙周病。

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.