Altering Cytokine mRNA Stability in Periodontal Bone Loss

改变牙周骨丢失中细胞因子 mRNA 的稳定性

• 批准号: 7615823
• 负责人: Keith L Kirkwood
• 金额: $ 9.56万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615823
• 关键词: 3' Untranslated Regions; Abbreviations; Acid Phosphatase; Actinobacillus actinomycetemcomitans; Address; Adenosine; Alveolar Bone Loss; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Binding Proteins; Bone Marrow; Cells; Chronic; Complex; Cytokine Gene; Data; Dinoprostone; Disease; Elements; Forsythia; Fusobacterium nucleatum; Gene Targeting; Granulocyte-Macrophage Colony-Stimulating Factor; Green Fluorescent Proteins; Immune; Immunohistochemistry; In Vitro; Indium; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Interleukins; Lipopolysaccharides; MAP Kinase Gene; MAPK14 gene; Matrix Metalloproteinases; Membrane; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Mus; NF-kappa B; Oral; PTGS2 gene; Pathway interactions; Periodontal Diseases; Periodontitis; Phosphotransferases; Plasmids; Process; Production; Property; Protein Binding; Protein Kinase; Protein Overexpression; Proteins; Purpose; RNA Splicing; Regulation; Resistance; Role; Signal Transduction; Stress; T-Lymphocyte; TIS11 protein; TNF gene; TNFSF11 gene; Therapeutic; Toll-like receptors; Treponema denticola; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Untranslated Regions; Uridine; X-Ray Computed Tomography; ZFP36L2 gene; Zinc Fingers; base; bone; bone loss; butyrate response factor 1; collagenase 3; cyclooxygenase 2; cytokine; genetic regulatory protein; human TNF protein; human ZFP36L2 protein; in vivo; mRNA Decay; mRNA Expression; mRNA Stability; mRNA Transcript Degradation; macrophage; oral pathogen; pathogen; pathogenic bacteria; receptor

DESCRIPTION (provided by applicant): Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The production of inflammatory cytokines is a highly regulated process involving transcriptional and posttranscriptional mechanisms. At the posttranscriptional level, the presence of adenosine/uridine-rich elements (AREs) in the 3' untranslated region of many cytokine genes, including IL-6, TNF-a, and COX-2, targets the mRNA for rapid degradation. As a consequence, cytokine production is repressed. Tristetraprolin (TTP) is a zinc finger protein that binds to the ARE of cytokine mRNAs and enhances degradation of the mRNA. TTP is phosphorylated by the p38-MK2 pathway and may serve as a general mechanism of cytokine mRNA regulation. We have recently shown that LPS-induced IL-6 mRNA stability expression requires p38 signaling. Preliminary data for this proposal indicates that TTP transfected cells inhibit LPS-induced IL-6 expression. Based upon these data, we hypothesize that the mRNA decay enhancing properties of TTP may be exploited for potential anti-inflammatory purposes. In this proposal, the ability of TTP over-expression to decrease inflammation will be determined in vitro using gene targeted strategies in macrophages, and in vivo using experimental periodontitis models. The specific aims are 1) to clarify the role of TTP on IL-6, TNF, and COX-2 mRNA expression and stability in vitro and 2) determine the impact of TTP in inflammatory and periodontal pathogen- initiated bone destruction in vivo using TTP-/- mice. These studies will establish the role of LPS-induced cytokine mRNA stability in inflammatory bone loss through selective mRNA decay targeting with TTP. Upon the accomplishment of these aims, subsequent studies will address the potential of TTP as a therapeutic strategy to control periodontal bone loss in small animal models. Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. These studies will establish the role of host immune proteins termed cytokines and the regulation of cytokines at the level of mRNA stability in inflammatory bone loss through selective mRNA decay targeting with a protein that regulates cytokine mRNA stability. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases and other chronic inflammatory diseases.

描述（由申请人提供）：牙周病的发生和进展是宿主对口腔病原体的免疫炎症反应的结果。炎症细胞因子的产生是一个高度调控的过程，涉及转录和转录后机制。在转录后水平，许多细胞因子基因（包括 IL-6、TNF-a 和 COX-2）的 3' 非翻译区中存在富含腺苷/尿苷的元件 (ARE)，可靶向 mRNA 进行快速降解。结果，细胞因子的产生受到抑制。 Tristetraprolin (TTP) 是一种锌指蛋白，可与细胞因子 mRNA 的 ARE 结合并增强 mRNA 的降解。 TTP 由 p38-MK2 途径磷酸化，可能作为细胞因子 mRNA 调节的一般机制。我们最近发现 LPS 诱导的 IL-6 mRNA 稳定表达需要 p38 信号传导。该提议的初步数据表明，TTP 转染细胞抑制 LPS 诱导的 IL-6 表达。基于这些数据，我们假设 TTP 的 mRNA 衰减增强特性可用于潜在的抗炎目的。在该提案中，将使用巨噬细胞中的基因靶向策略在体外确定 TTP 过度表达减少炎症的能力，并使用实验性牙周炎模型在体内确定。具体目标是 1) 阐明 TTP 在体外对 IL-6、TNF 和 COX-2 mRNA 表达和稳定性的作用，以及 2) 使用 TTP 确定 TTP 在体内炎症和牙周病原体引发的骨破坏中的影响-/- 老鼠。这些研究将通过 TTP 选择性 mRNA 衰减来确定 LPS 诱导的细胞因子 mRNA 稳定性在炎症性骨质流失中的作用。实现这些目标后，后续研究将探讨 TTP 作为控制小动物模型牙周骨丢失的治疗策略的潜力。牙周病的发生和进展是宿主对口腔病原体免疫炎症反应的结果。这些研究将确定被称为细胞因子的宿主免疫蛋白的作用，以及通过以调节细胞因子 mRNA 稳定性的蛋白质为目标的选择性 mRNA 衰变，在 mRNA 稳定性水平上调节细胞因子在炎症性骨质流失中的作用。了解转录后细胞因子调节在牙周炎症和骨质流失中的作用的进展可能为牙周病和其他慢性炎症性疾病的治疗带来新的可能性。