The Role of Histone Deacetylase 6 in Oral Bacteria-Mediated Periodontal Inflammation

组蛋白脱乙酰酶 6 在口腔细菌介导的牙周炎症中的作用

• 批准号: 10594425
• 负责人: Hannah Lohner
• 金额: $ 4.16万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-25 至 2025-03-24
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594425
• 关键词: Adult; Affect; Alveolar Bone Loss; Area; Attenuated; Award; Bacteria; Bacterial Infections; Binding; Bone Resorption; CXCL2 gene; Cell Nucleus; Cells; Chronic; Cytoplasm; Data; Deacetylation; Disease; Disease Progression; Economics; Elements; Enzymes; Equilibrium; FOXO1A gene; Fellowship; Fusobacterium nucleatum; Genes; Genetic Transcription; Gingiva; Goals; HDAC6 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Immune; Immune response; Immunology; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-12; Interleukin-6; Invaded; Knockout Mice; Macrophage; Measures; Mediating; Methods; Microbe; Microbiology; Modeling; Molecular; Molecular Biology; Mus; Neutrophil Infiltration; Nuclear Translocation; Oral; Osteitis; Patients; Pattern; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Phosphorylation; Play; Population; Porphyromonas gingivalis; Process; Production; Protein Acetylation; Proteomics; Quality of life; Reaction; Regulation; Reporting; Research; Rheumatoid Arthritis; Role; Severities; Signal Pathway; Signal Transduction; TNF gene; Testing; Tissues; Tooth Loss; Training; United States; Virus; Work; alveolar bone; bone loss; career; chronic inflammatory disease; cytokine; experience; experimental study; gain of function; improved; in vivo; inhibitor; insight; loss of function; member; microorganism; migration; model organism; neutrophil; new therapeutic target; non-histone protein; novel; novel therapeutic intervention; oral bacteria; oral infection; pathogen; pathogenic bacteria; prevent; promoter; response; subcutaneous; therapeutic target; transcription factor; transcriptomics

Project Summary/Abstract: Periodontitis is a chronic inflammatory disease induced by bacterial infection within the periodontium and affects almost 50% of adults in the United States. Unresolved inflammation in this area results in the breakdown of the periodontal ligament and alveolar bone which can lead to subsequent tooth loss. While the presence of bacteria initiates periodontitis, it is ultimately not the sole factor that drives disease progression. The inflammatory response is critical for the eradication of bacterial invaders, however the dysregulation of these mechanisms and overproduction of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12 p40, and Macrophage Inflammatory Protein 2 (MIP-2) have been implicated in the progression of tissue damage in the periodontium and in other chronic inflammatory diseases. Histone deacetylase 6 (HDAC6) is a member of the class II HDACs located in the cytoplasm that can deacetylate specific non-histone proteins and facilitate their translocation to the nucleus. This deacetylation has been reported to alter production of inflammatory mediators in response to the stimulation of microbe-associated molecular patterns (MAMPs). Our preliminary results have shown that stimulation of innate immune cells with Porphyromonas gingivalis, a major pathogenic bacterium associated with chronic periodontitis, resulted in phosphorylation of class II HDACs and subsequent deacetylation of FoxO1, which will enhance its binding to the FoxO-binding element and thus promote associated pro-inflammatory mediator production. Likewise, selective inhibition of HDAC6 resulted in a decrease in pro-inflammatory cytokine production through increasing cytosolic translocation of FoxO1 and subsequently decreased its binding to the promoter of C/EBP-β after P. gingivalis infection. Therefore, using P. gingivalis as a model organism, we hypothesize that oral bacterial pathogens activate HDAC6 and enhance the inflammatory response through facilitating the deacetylation and nuclear translocation of FoxO1, subsequently enhancing the expression of downstream pro-inflammatory mediators. We will test this hypothesis using two aims. Experiments proposed for Aim 1 will investigate the role of HDAC6 in the inflammatory response by observing the production of inflammatory cytokines and the migration of neutrophils and will also delineate the downstream signaling of HDAC6 in different immune cells in response to P. gingivalis challenge. In Aim 2, we will examine the in vivo relevancy of HDAC6 signaling in gingival tissue inflammatory responses to oral bacterial infection and alveolar bone loss. These aims will establish the regulatory function of HDAC6-mediated differential inflammatory mediator secretion in the control of immune responses. The long-term goal of this proposed work will be to identify novel interventional therapeutic targets and regulatory mechanisms of periodontal inflammation that may be broadly applicable to other inflammatory diseases.

项目摘要/摘要： 牙周炎是牙周感染引起的一种慢性炎症性疾病，并影响 在美国，几乎有50％的成年人。该领域未解决的炎症导致 牙周韧带和牙槽骨，可能导致随后的牙齿脱落。而细菌的存在 启动牙周炎，最终不是驱动疾病进展的唯一因素。炎症 反应对于细菌侵略者的逃生者至关重要，但是这些机制的失调和 促炎性细胞因子（例如TNF-α，IL-6，IL-12 p40和巨噬细胞炎症）的过量生产 蛋白2（MIP-2）在牙周和其他组织中组织损伤的进展中隐含 慢性炎症性疾病。组蛋白脱乙酰基酶6（HDAC6）是位于II类HDAC的成员 可以脱乙酰化特异性非固定蛋白并促进其转移到细胞核的细胞质。 据报道，这种脱乙酰化会改变炎症介质的产生，以应对刺激 微生物相关的分子模式（MAMP）。我们的初步结果表明，刺激 先天性免疫细胞与卟啉单胞菌，这是一种主要的致病细菌 牙周炎，导致II类HDACs的磷酸化和随后的FOXO1脱乙酰基化，这将是 增强其与FOXO结合元件的结合，从而促进相关的促炎性介体 生产。同样，选择性抑制HDAC6导致促炎细胞因子的降低 通过增加FOXO1的胞质易位生产，随后降低了其与 牙龈疟原虫感染后C/EBP-β的启动子。因此，将牙龈疟原虫作为模型生物，我们 假设口服细菌病原体会激活HDAC6并增强炎症反应 通过促进FOXO1的脱乙酰基化和核易位，随后增强了 下游促炎介体的表达。我们将使用两个目标检验这一假设。 提出的AIM 1的实验将通过观察到HDAC6在炎症反应中的作用 炎性细胞因子的产生和中性粒细胞的迁移，也将描绘下游 HDAC6在响应牙龈疟原虫挑战的不同免疫细胞中的信号传导。在AIM 2中，我们将检查 HDAC6信号在牙龈组织炎症反应中对口腔细菌感染和 肺泡骨质流失。这些目标将确定HDAC6介导的差异炎症的调节功能 控制免疫反应的介体分泌。这项拟议工作的长期目标是 确定可能的新型介入治疗靶标和牙周感染的调节机制 广泛适用于其他炎症性疾病。