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.

项目概要 牙周炎会导致牙齿支持硬组织和软组织的不可逆转的损伤，影响着 42% 的美国人 这种极其流行的炎症性口腔疾病也与全身性疾病密切相关。 例如，临床研究表明牙周炎包含混合性疾病表型。 例如，约 20% 的牙周炎患者的疾病进展模式与其他牙周炎患者的疾病进展模式明显不同 最近，我们使用数据驱动的方法来创建牙周概况。 分类（PPC）-通过紧密结合牙周测量和指数来进行分期系统 经过社区队列的跟踪验证，我们证明了这个新的 PPC-Staging 工具具有显着的效果。 改善与糖尿病、中风和冠心病等多种系统性疾病的临床关联 通过蛋白质组生物标志物改善每个 PPC 阶段（I 至 VII）的同质性。 通过对队列患者的龈沟液进行分析，我们发现 干扰素-β (IFN-β) 细胞因子是 I 型干扰素 (IFN-I) 的经典成员，在 PPC 阶段中与 白细胞介素 1 受体拮抗剂 (IL-1RA)，一种广为人知的经典抗炎细胞因子。 我们发现这一发现促使我们使用小鼠牙周炎模型来评估 IFN-I 在牙周炎中的作用。 IFN-I对牙槽骨丢失具有保护作用，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-中性粒细胞轴的抑制相关，而 IL27 的转录在局部 IL-27 在完整的 IFN-I 通路中的作用仍有待阐明。 我们进一步表明 IFN-β 信号传导抑制了脂多糖诱导的牙周炎。 促炎细胞因子的产生并有效抑制骨髓中破骨细胞的分化 因此，我们认为单核细胞谱系中完整的 IFN-I 反应起着重要作用。 我们试图通过 IL-27 途径使 IL-17-神经细胞轴失活，从而在牙周炎中发挥保护作用。 深入了解 IFN-I 调节牙周先天性和适应性免疫反应的机制 我们建议通过以下方法检验这一中心假设：1）我们首先定义角色。 使用动物牙周炎模型2)我们将研究IL-17-中性粒细胞轴中的I型IFN-IL-27通路； 评估 IFN-I 信号传导在包含单核细胞/破骨细胞前体细胞的骨髓谱系中的具体作用 在牙周炎模型中；3）我们还将评估局部新颖的纳米颗粒介导的效果 我们的目标是在牙周炎模型中持续释放 IFN-β/IFN-I 刺激剂。 了解 INF-I（一种临床相关但尚未充分研究的分子）在牙周病中的作用，并 利用 IFN-β 或以 IFN-I 为中心的炎症网络作为生物标志物，进一步完善临床牙周 此外，该研究计划将为 IFN-Is 作为辅助治疗提供证据。 对一部分患者采取治疗措施，以改善精确的牙周健康。