Assessing the role of Type I Interferon (IFN-I) in Periodontal Disease

评估 I 型干扰素 (IFN-I) 在牙周病中的作用

• 批准号: 10558868
• 负责人: Shaoping Zhang
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558868
• 关键词: Abate; Address; Adult; Affect; Agonist; Alveolar Bone Loss; Animals; Anti-Inflammatory Agents; Biological; Biological Assay; Biological Markers; Bone Marrow; Bone Resorption; CD4 Positive T Lymphocytes; Cells; Classification; Clinical; Clinical Research; Communities; Complex; Control Animal; Coronary heart disease; Cyclic GMP; Cytokine Network Pathway; Data; Diabetes Mellitus; Disease; Disease Progression; Family member; Flow Cytometry; Genes; Genetic Transcription; Gingiva; Gingival Crevicular Fluid; Goals; Health; Heterogeneity; Human; IFNAR1 gene; IFNAR2 gene; IL17 gene; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Type I; Interferon-beta; Interferons; Interleukin-6; Knock-out; Knockout Mice; Ligation; Ligature; Lipopolysaccharides; LoxP-flanked allele; Macrophage; Measurement; Measures; Mediating; Mediator; Microinjections; Modeling; Mouth Diseases; Multiple Sclerosis; Mus; Myelogenous; Nature; Neutrophil Activation; Neutrophil Infiltration; Osteoclasts; Pathway interactions; Patients; Pattern; Periodontal Diseases; Periodontitis; Phenotype; Play; Population; Predisposition; Prevalence; Production; Proteomics; Research; Research Proposals; Role; Signal Transduction; Staging; Staging System; Stroke; System; Systemic disease; Testing; Therapeutic; Time; Tissues; Tooth Loss; Tooth structure; Validation; Viral Physiology; Wild Type Mouse; adaptive immune response; anakinra; bone loss; cell type; clay; clinically relevant; cohort; conditional knockout; cytokine; disease classification; disease phenotype; follow-up; improved; in vivo; indexing; insight; member; monocyte; nano; nanoparticle; neutrophil; novel; osteoclastogenesis; patient subsets; precursor cell; receptor; response; tool; translational research program

Project Summary Periodontitis, which results in irreversible damage in hard and soft tooth-supporting tissues, affects 42% US adults. This extremely prevalent inflammatory oral disease is also tightly associated with systemic diseases such as diabetes. Clinical studies have shown that periodontitis contains mixed disease phenotypes. For example, the disease progression pattern in about 20% of periodontitis patients is clearly distinct from that of the majority in a population. Recently, we used a data-driven approach to create a periodontal profile classification (PPC)-Staging system by integrating periodontal measurements and indices from a closely followed up community cohort. After validation, we demonstrated that this new PPC-Staging tool has drastically improved clinical associations with several systemic diseases including diabetes, stroke, and coronary heart disease due to the improved homogeneity of each PPC-Stage (I to VII). Through a proteomic biomarker analysis in the gingival crevicular fluid of a patient pool from the cohort, we found that the expression pattern of the interferon-β (IFN-β) cytokine, a classical member of type I interferon (IFN-I), in PPC-Stages mimics that of interleukin-1 receptor antagonist (IL-1RA), a well-described classical anti-inflammatory cytokine. This novel finding prompted us to evaluate the role of IFN-I in periodontitis. Using a mouse periodontitis model, we found that IFN-I plays a protective role in alveolar bone loss. We further found that such a protective role of IFN-I is associated with a dampening of an interleukin (IL)-17-neutropphil axis, while the transcription of Il27 in local gingiva was upregulated. The role of IL-27 in an integral IFN-I pathway has yet remained to be elucidated in periodontitis. We further showed that IFN-β signaling suppressed the lipopolysaccharide-induced proinflammatory cytokine production in and potently inhibited osteoclast differentiation from bone marrow- derived monocytes. We therefore hypothesize that an integral IFN-I response in monocytic lineage plays a protective role in periodontitis by deactivating an IL-17-neurophil axis through an IL-27 pathway. We seek to gain insight into the mechanism of IFN-I in modulating innate and adaptive immune responses in periodontal disease. We propose to test this central hypothesis by the following approaches: 1) we will first define the role of Type I IFN- IL-27 pathway in IL-17-neutrophil axis using the animal periodontitis model; 2) we will then assess the specific role of IFN-I signaling in myeloid lineage that contains monocytic /osteoclast precursor cells in the periodontitis model; 3) we will also evaluate the effect of a locally delivered novel nanoparticle-mediated sustained release of IFN-β/IFN-I stimulator in the periodontitis model. Our goal of this project is to advance the understanding of INF-I, a clinically relevant yet under-investigated molecule, in periodontal disease, and to leverage IFN-β or IFN-I-centered inflammatory networks as biomarkers to further refine the clinical periodontal disease classification. In addition, this research proposal will provide evidence to target IFN-Is as an adjunctive therapeutic measure in a subset of patients to improve precision periodontal health.

项目摘要 牙周炎，导致不可逆的损害，在硬和软牙齿支持组织，影响42%的美国 成年人了这种极其普遍的炎症性口腔疾病也与全身性疾病密切相关 例如糖尿病。临床研究表明，牙周炎包含混合疾病表型。为 例如，约20%的牙周炎患者的疾病进展模式与牙周炎患者的疾病进展模式明显不同。 人口中的大多数。最近，我们使用数据驱动的方法来创建牙周概况 分类（PPC）-分期系统，通过整合牙周测量和指数，从一个密切的 跟进社区队列。经过验证，我们证明了这个新的PPC分期工具， 改善与几种全身性疾病（包括糖尿病、中风和冠心病）的临床相关性 由于每个PPC阶段（I至VII）的均匀性改善而导致的疾病。通过蛋白质组生物标志物 通过对来自队列的患者池的龈沟液的分析，我们发现， 干扰素-β（IFN-β）细胞因子是I型干扰素（IFN-I）经典成员，在PPC阶段模拟 白细胞介素-1受体拮抗剂（IL-1 RA），一种被充分描述的经典抗炎细胞因子。这本小说 这一发现促使我们评估IFN-I在牙周炎中的作用。使用小鼠牙周炎模型，我们发现 IFN-I在牙槽骨丢失中起保护作用。我们进一步发现，IFN-I的这种保护作用是 与白细胞介素（IL）-17-嗜中性粒细胞轴的抑制相关，而IL 27在局部的转录 牙龈被上调。IL-27在IFN-I整体途径中的作用仍有待阐明 牙周炎我们进一步表明IFN-β信号转导抑制了脂多糖诱导的细胞凋亡。 促炎细胞因子的产生并有效抑制骨髓中破骨细胞的分化， 衍生的单核细胞。因此，我们推测，在单核细胞谱系中，IFN-Ⅰ应答在单核细胞中起着重要作用。 通过IL-27途径使IL-17-嗜神经细胞轴失活而在牙周炎中起保护作用。我们寻求 深入了解IFN-I调节牙周先天性和适应性免疫反应的机制 疾病我们建议通过以下方法来测试这个中心假设：1）我们将首先定义角色 I型IFN-IL-27通路在IL-17-中性粒细胞轴中的作用; 2）然后我们将 评估IFN-I信号在含有单核细胞/破骨细胞前体细胞的髓系中的特定作用 在牙周炎模型中; 3）我们还将评估局部递送的新型纳米颗粒介导的 牙周炎模型中IFN-β/IFN-I刺激剂的持续释放。我们这个项目的目标是推进 了解INF-I，一种临床相关但研究不足的分子，在牙周病中， 利用以IFN-β或IFN-1为中心的炎症网络作为生物标志物， 疾病分类此外，这项研究计划将为靶向IFN-γ作为一种免疫抑制剂提供证据。 治疗措施的一个子集的患者，以改善精确牙周健康。