Epigenetic Regulation of Periodontal Inflammation

牙周炎症的表观遗传调控

基本信息

批准号：
10327674
负责人：
Zhao Lin
金额：
$ 36.58万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10327674
关键词：
Acetylation Affect Age Alveolar Bone Loss American Animal Model Antibiotic Therapy BRD2 gene Binding Bone Resorption Bromodomain Cardiovascular Diseases Cells Chromatin Clinical Data Complex Data Debridement Development Disease Disease Progression Ecosystem Environmental Exposure Epigenetic Process Epithelial Cells Foundations Gene Expression Gene Expression Regulation Genes Genetic Transcription Gingiva Harvest Health Histone Acetylation Histones Human Immune Immune response Inflammation Inflammatory Injections Innovative Therapy Knowledge Ligation Ligature Lysine Mechanics Mediating Microbial Biofilms Modeling Modification Molecular Mus Oral Osteoclasts Osteogenesis Pathogenesis Patients Pattern Periodontal Diseases Periodontitis Peripheral Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacologic Substance Phase III Clinical Trials Play Population Porphyromonas gingivalis Predisposition Production Rattus Reader Recurrence Reporting Role Severities Site Smoking Societies Tertiary Protein Structure Testing Therapeutic Effect Tissues Tooth Loss Tooth structure Transcription Initiation Transcriptional Activation aged base chromatin modification clinical application cytokine diagnostic biomarker disorder control driving force dysbiosis epigenetic drug epigenetic regulation experimental study gene network genome-wide genomic locus histone modification in vivo inhibitor loss of function microbial microbial community microbiome microbiota novel novel therapeutics oral cavity epithelium pathogen prevent programs protein expression public health relevance reconstruction recruit response small molecule standard of care subgingival microbiome targeted treatment transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Periodontitis is initiated by a dysbiotic microbial community; however, it is the host immune response to the microbial insults that ultimately causes the damage to the tooth supporting complex. There are considerable limitations to the current standard of care for treatment of periodontal diseases, which is focused on eliminating the biofilms. Increasing evidence indicates that the susceptibility to periodontitis is largely determined by the host response. Therapies targeting the uncontrolled, overly aggressive inflammation are critical not only for blocking the diseases but also for the reconstruction of a healthy periodontal ecosystem. Epigenetic regulation such as histone acetylation is essential for inflammatory gene expression. A specific histone acetylation pattern is proposed in inflammatory diseases including periodontitis. Bromodomain and extraterminal domain (BET) proteins are the “reader” that mediate the epigenetic marks to the transcription machinery. BET inhibitors are an emerging class of epigenetic drugs for inflammatory diseases. Recently, we found that RVX-208, a selective BET inhibitor that is being tested in a Phase 3 clinical trial for cardiovascular diseases, significantly suppresses inflammatory cytokine production and inhibits osteoclast differentiation. These findings suggested that histone acetylation and BET proteins may have important roles in periodontal inflammation, and may be potential diagnostic markers and pharmaceutical targets for periodontitis. To better understand epigenetic regulation in periodontitis and develop a novel therapeutic for periodontitis, we propose to 1) Identify the histone acetylation and BET protein expression profile in periodontitis patients; 2) Define the role of BET proteins in periodontal inflammation; 3) Determine if targeting histone acetylation by a selective BET inhibitor can ameliorate periodontal inflammation and alveolar bone loss in vivo. The proposed studies will generate critical clinical data to support the importance of epigenetic regulation in the pathogenesis of periodontal disease and help us develop the first “epi” drug to treat the diseases. 1

项目摘要/摘要牙周炎由不植物微生物群落引发；但是，这是宿主对微生物损伤最终会损害牙齿支撑复合物。有很多牙周疾病治疗当前护理标准的局限性，该标准的重点是消除生物膜。越来越多的证据表明，牙周炎的易感性在很大程度上由宿主确定回复。针对不受控制的疗法，过度激进的炎症不仅对阻塞至关重要这些疾病也是为了重建健康的牙周生态系统。表观遗传调节，例如组蛋白乙酰化对于炎症基因表达至关重要。特定的组蛋白乙酰化模式是提出的炎症性疾病包括牙周炎。溴化域和外交结构域（BET）蛋白质是将表观遗传标记介导转录机械的“读取器”。 BET抑制剂是新兴的表观遗传药物用于炎症性疾病。最近，我们发现RVX-208是一种选择性在第三阶段临床试验中针对心血管疾病进行测试的BET抑制剂，可显着抑制炎性细胞因子产生并抑制破骨细胞分化。这些发现表明组蛋白乙酰化和BET蛋白可能在牙周感染中具有重要作用，并且可能是潜在的牙周炎的诊断标记和药物靶标。更好地了解表观遗传调节牙周炎并开发新的牙周炎疗法，我们建议1）确定组蛋白乙酰化牙周炎患者中的BET蛋白表达谱； 2）定义BET蛋白在牙周上的作用炎; 3）确定通过选择性BET抑制剂靶向组蛋白乙酰化是否可以改善牙周体内炎症和肺泡骨质流失。拟议的研究将产生关键的临床数据以支持表观遗传调节在牙周疾病发病机理中的重要性，并帮助我们发展第一个 “ EPI”药物治疗疾病。 1