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: 7483844
• 负责人: CUN-YU WANG
• 金额: $ 33.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483844
• 关键词: Apoptosis; Bacteria; Bacterial Infections; Cell Line; Chronic; Complex; Diagnosis; Dominant-Negative Mutation; ERG gene; Gene Expression Profile; Genes; Genetic Transcription; Genome; Genomics; Gingiva; Human; Immune response; Immunity; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Interleukin-1; Lipopolysaccharides; Mediating; Mediator of activation protein; Membrane; Microarray Analysis; Molecular; NF-kappa B; NFKB Signaling Pathway; Pathogenesis; Pathway interactions; Periodontal Diseases; Periodontitis; Personal Satisfaction; Phosphotransferases; Play; Porphyromonas gingivalis; Prevention; Protein Array; Proteomics; Receptor Signaling; Regulation; Relative (related person); Research Personnel; Retroviridae; Role; Signal Pathway; Signal Transduction; TNF gene; Tissue Microarray; Tissues; Toll-like receptors; activating transcription factor; base; cytokine; inhibitor/antagonist; monocyte; novel; pathogen; programs; protein expression; response; transcription factor; 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）：本申请的长期目标是利用基因组和蛋白质组学方法了解 NF-kB（核因子 kappa B）在牙周疾病分子发病机制中的作用。 NF-kB 是一种转录因子，调节多种与炎症、免疫和宿主反应相关的立即早期反应基因。牙周病是慢性革兰氏阴性厌氧菌感染，导致牙龈炎症和牙周组织破坏。包括牙龈卟啉单胞菌（P.gingivalis）在内的几种细菌与牙周炎的发生和恶化有关。 LPS 是这些细菌外膜的主要成分，是宿主炎症和免疫反应最有效的引发剂之一，可导致牙周支持组织的破坏。最近，转导 LPS 信号传导的 Toll 样受体 (TLR) 复合物已被鉴定。 LPS/TLR 相互作用可转导信号级联反应以激活 NF-kB，从而开启炎症介质的转录。尽管 TLR 信号复合物已得到很好的表征，但 NF-kB 激活和信号传导的精确机制尚未得到充分研究。鉴于 NF-κB 在炎症和宿主反应中的关键作用，NF-κB 很可能在牙周炎的分子发病机制中发挥重要作用。为了更好地了解 NF-kB 在牙周炎分子发病机制中的作用，我们建议使用基因组和蛋白质组学方法对 NF-kB 介导的基因和 P. gingivalis LPS 刺激的细胞内信号通路进行全球剖析。在目标 1 和目标 2 中，我们建议在全基因组范围内鉴定由经典和非经典 NF-kB 信号通路调节的牙龈卟啉单胞菌 LPS 诱导的基因，并探索如何使用基因组来调节 NE-kB 依赖性转录。和蛋白质组学方法。在目标 3 中，我们将使用组织微阵列和蛋白质阵列确定经典和非经典 NF-kB 信号通路在发炎的牙周组织中是否被激活，并探讨它们的激活是否与牙龈卟啉单胞菌 LPS 诱导的基因表达谱相关。我们研究的新发现将对牙周病的预防、诊断和治疗产生重要影响。