Induction of intergrating NF-kB by P gingivalis LPS

牙龈卟啉单胞菌 LPS 诱导整合 NF-kB

• 批准号: 6866422
• 负责人: CUN-YU WANG
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866422
• 关键词: Bacteroides gingivalis; biological signal transduction; clinical research; genetic regulation; genetic transcription; gingiva; gingivitis; human subject; in situ hybridization; inflammation; lipopolysaccharides; microarray technology; molecular pathology; nuclear factor kappa beta; patient oriented research; periodontitis; periodontium; toll like receptor; yeast two hybrid system

DESCRIPTION (provided by applicant): The long-term objective of this application is to understand the role of NF-kB (nuclear factor kappa B) in the molecular pathogenesis of periodontal diseases using genomic and proteomic approaches. NF-kB is a transcription factor which regulates a variety of immediate early response genes associated with inflammation, immunity and host responses. Periodontal diseases are chronic Gram-negative anaerobic bacterial infections leading to inflammation of the gingiva and destruction of periodontal tissues. Several bacteria including Porphyromonos gingiva/is (P. gingivalis) have been implicated in the initiation and exacerbation of periodontitis. LPS, a major component of the outer membrane of these bacteria, is one of the most potent initiators of host inflammatory and immunological response which results in destruction of periodontal supporting tissue. Recently, the Toll-like receptor (TLR) complex which transduces LPS signaling has been identified. LPS/TLR interaction transduces signaling cascades to activate NF-kB which turns on transcription of inflammatory mediators. Although the TLR signaling complex has been well characterized, the precise mechanisms of NF-kB activation and signaling have not been well studied. Given the critical role of NF-KB in inflammation and host response, NF-kB is likely to play an important role in the molecular pathogenesis of periodontitis. To better understand the role of NF-kB in the molecu]ar pathogenesis of periodontitis, we propose to globa1ly dissect NF-kB-mediated genes and intracellular signaling pathways stimulated by P. gingivalis LPS using genomic and proteomic approaches. In Aim 1 and Aim 2, we propose to identify P. gingivalis LPS-induced genes regulated by the canonical and non-canonical NF-kB signling pathways on a genome wide basis and explore how the NE-kB-dependent transcription is regulated using genomic and proteomic approaches. In Aim 3, we will determine whether the canonical and non-canonical NF-kB signaling pathways are activated in inflamed periodontal tissues and explore whether their activation is associated with the gene expression profile induced by P. gingivalis LPS using tissue microarray and protein array. The novel findings from our studies will have important implications in the prevention, diagnosis and treatment of periodontal diseases.

描述（由申请人提供）：本应用的长期目标是了解NF-KB（核因子Kappa B）在使用基因组和蛋白质组学方法的牙周疾病分子发病机理中的作用。 NF-KB是转录因子，可调节与炎症，免疫和宿主反应相关的各种直接的早期反应基因。牙周疾病是慢性革兰氏阴性厌氧细菌感染，导致牙龈发炎和牙周组织的破坏。包括牙龈卟啉单胞菌/IS（牙龈疟原虫）在内的几种细菌已与牙周炎的开始和加剧有关。 LPS是这些细菌外膜的主要组成部分，是宿主炎症和免疫反应的最有效的启动者之一，导致牙周支撑组织破坏。最近，已经鉴定出传递LPS信号传导的Toll样受体（TLR）复合物。 LPS/TLR相互作用会导出信号级联反应以激活NF-KB，从而打开炎症介质的转录。尽管TLR信号传导复合物已经很好地表征，但NF-KB激活和信号传导的精确机制尚未得到很好的研究。鉴于NF-KB在炎症和宿主反应中的关键作用，NF-KB可能在牙周炎的分子发病机理中起重要作用。为了更好地理解NF-KB在牙周炎的分子发病机理中的作用，我们建议使用基因组和蛋白质组学方法刺激了gingivalis lps刺激的NF-KB介导的基因和细胞内信号传导途径。在AIM 1和AIM 2中，我们建议在基因组广泛的基因组中鉴定由规范和非基因NF-KB签名途径调节的基因，并探索如何使用基因组和蛋白质组学方法调节NE-KB依赖性转录。在AIM 3中，我们将确定在发炎的牙周组织中是否激活了规范和非典型的NF-KB信号通路，并探讨了它们的激活是否与使用组织微阵列和蛋白质阵列的Gingivalis LPS诱导的基因表达谱相关。我们研究的新发现将对牙周疾病的预防，诊断和治疗具有重要意义。