Epithelial Innate Immune Response to Oral Bacteria

描述：本应用程序将分析宿主牙龈上皮细胞（GECs）在对共生和致病性口腔细菌的反应中利用的分子机制，以及牙周组织中与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。它们也产生天然的抗微生物肽-防御素家族。防御素抗菌肽是先天免疫系统的一部分，这是一套复杂的反应，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）在gec中表达上调，以应对共生菌和致病菌。此外，这种肽在正常口腔黏膜中广泛表达，与正常表皮不同，这表明正常口腔上皮的先天免疫反应处于更高的准备状态。该应用将验证以下假设：口腔共生细菌和致病性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的先天免疫状态，以增加对环境和随后暴露于病原体的反应性，p-防御素是这种增强的先天免疫反应的主要影响因素。这些假设建立在以下证据的基础上：共生菌和致病菌利用不同的信号通路调节hBD-2基因表达，并且hBD-2本身影响先天免疫反应并作为一种积极的自分泌调节剂。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。最后的目的是研究这些受体对牙龈卟啉单胞菌的反应信号的功能，卟啉单胞菌是一种主要的牙周病病原体，蛋白酶是其毒力因子的一部分。这些问题和假设将被检验，目的是更好地了解gec对共生细菌和致病菌的整体反应，强调基因表达程序和受体对先天免疫反应至关重要。这项工作将为确定新的治疗靶点以预防和治疗牙周病奠定基础。

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.