Protease-activated receptor signaling in oral innate im*

口腔先天性免疫中的蛋白酶激活受体信号传导*

• 批准号: 6873764
• 负责人: BEVERLY A DALE-CRUNK
• 金额: $ 22.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873764
• 关键词: Bacteroides gingivalis; bacteria infection mechanism; biological signal transduction; clinical research; endopeptidases; epithelium; fibroblasts; gene expression; host organism interaction; human tissue; immune response; inflammation; microarray technology; oral bacteria; periodontium disorder; phagocytosis; polymerase chain reaction; thrombin; thrombin receptor; tissue /cell culture; virulence

DESCRIPTION (provided by applicant): This exploratory proposal will utilize genomic techniques to analyze the molecular interactions that occur between oral bacteria and host epithelial cells associated with the pathogenesis of periodontal disease. Studies will focus on the role of the proteinase-activated receptor (PAR) family in signaling innate immune and inflammatory responses by gingival epithelial cells. Members of this family of receptors are expressed on both gingival epithelial cells and fibroblasts. These receptors signal the presence of danger in the environment, contribute to inflammation and to enhance epithelial cell phagocytosis. However, their role in periodontal disease is poorly understood. Multiple factors produced during the chronic inflammatory response appear to be major factors in the tissue destruction that occurs in periodontal disease. The major microbial species associated with periodontal disease all have proteinases as part of their set of virulence factors. The studies of this proposal will lay the groundwork for further studies on the role of PARs, define a possible new molecular mechanism for pathogenesis of disease, and open the way to understanding new therapeutic targets to prevent or treat periodontal diseases. This work will test the hypotheses (1) that PARs are involved in innate immune function in gingival epithelium and (2) that signaling via PAR-1 and PAR-2 (the most highly expressed members of this family) differentially contributes to the innate immune response in these cells thereby activating different networks of response genes. This work will also examine the possible role of PARs in the recognition of both commensal and pathogenic oral bacteria by gingival epithelial cells. The aims of the proposal are (1) to characterize the involvement of PAR signaling in upregulation of human beta-defensin-2 and other markers of innate immune activation in oral epithelial cells using the PAR-1 activator, thrombin, and PAR-2 peptide agonist peptide, SLIGRL-NH2, and oral pathogenic and commensal bacteria and (2) to utilize gene array analysis to test the hypothesis that PAR-1 and PAR-2 signaling differentially contributes to the innate immune response in gingival epithelial cells to activate different networks of response genes.

描述（由申请人提供）：该探索性提案将利用基因组技术来分析口腔细菌和宿主上皮细胞之间发生的与牙周病发病机制相关的分子相互作用。研究将重点关注蛋白酶激活受体（PAR）家族在牙龈上皮细胞发出先天免疫和炎症反应信号中的作用。该受体家族的成员在牙龈上皮细胞和成纤维细胞上表达。这些受体发出环境中存在危险的信号，导致炎症并增强上皮细胞的吞噬作用。然而，人们对它们在牙周病中的作用知之甚少。慢性炎症反应期间产生的多种因素似乎是牙周病中发生的组织破坏的主要因素。与牙周病相关的主要微生物种类都含有蛋白酶作为其毒力因子组的一部分。该提案的研究将为进一步研究PARs的作用奠定基础，定义疾病发病机制的可能新分子机制，并为了解预防或治疗牙周病的新治疗靶点开辟道路。这项工作将检验以下假设：(1) PAR 参与牙龈上皮的先天免疫功能，(2) 通过 PAR-1 和 PAR-2（该家族中表达最高的成员）发出的信号对先天免疫有不同的贡献这些细胞中的反应从而激活不同的反应基因网络。这项工作还将研究 PAR 在牙龈上皮细胞识别共生和致病性口腔细菌中的可能作用。该提案的目的是 (1) 使用 PAR-1 激活剂、凝血酶和 PAR-2 肽来表征 PAR 信号传导在上调人类 β-防御素-2 和口腔上皮细胞中先天免疫激活的其他标志物中的参与情况激动剂肽、SLIGRL-NH2 以及口腔致病菌和共生菌，以及 (2) 利用基因阵列分析来检验 PAR-1 和 PAR-2 信号传导对口腔致病菌和共生菌有不同贡献的假设牙龈上皮细胞的先天免疫反应激活不同的反应基因网络。