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

项目摘要 牙周炎会对支持牙齿的硬组织和软组织造成不可逆转的损害，影响美国42%的人 成年人。这种极其普遍的炎症性口腔疾病也与系统性疾病密切相关。 比如糖尿病。临床研究表明，牙周炎具有混合疾病表型。为 例如，大约20%的牙周炎患者的疾病进展模式与 人口中的大多数。最近，我们使用一种数据驱动的方法来创建牙周轮廓 分类(PPC)-紧密结合牙周测量和指数的分期系统 跟踪社区队列。经过验证，我们证明了这个新的PPC升级工具在很大程度上 改善与包括糖尿病、中风和冠心病在内的几种系统性疾病的临床相关性 疾病是由于每一PPC阶段(一至七)的同质性得到改善所致。通过蛋白质组生物标记物 对队列中的一名患者的牙周沟液进行分析，我们发现其表达模式 干扰素-β(干扰素-β)细胞因子是I型干扰素的经典成员，在PPC阶段模拟 白介素1受体拮抗剂(IL-1RA)是一种经典的抗炎细胞因子。这部小说 这一发现促使我们评估干扰素-I在牙周炎中的作用。使用小鼠牙周炎模型，我们发现 干扰素-I在牙槽骨丢失中起到保护作用。我们进一步发现，干扰素-I的这种保护作用是 与白细胞介素17-中性粒细胞轴抑制有关，而局部IL27的转录 牙周炎患者牙周组织明显升高。IL-27在完整的干扰素-I途径中的作用仍有待阐明。 牙周炎。我们进一步表明，干扰素-β信号转导抑制了内毒素诱导的 促炎症细胞因子的产生并有效地抑制骨髓向破骨细胞分化- 衍生的单核细胞。因此我们假设，在单核细胞系中，完整的干扰素-I反应发挥着 通过IL-27途径抑制IL-17-嗜神经细胞轴在牙周炎中的保护作用。我们寻求 深入了解干扰素-I调节牙周固有免疫和获得性免疫反应的机制 疾病。我们建议通过以下方法来检验这一中心假设：1)我们将首先定义角色 使用动物牙周炎模型研究IL-17-中性粒细胞轴中I型干扰素-IL-27途径；2)然后我们将 评估干扰素-I信号在含有单核细胞/破骨细胞前体细胞的髓系中的特殊作用 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的效果 干扰素-β/干扰素-I刺激物在牙周炎模型中的缓释作用我们这个项目的目标是推进 了解干扰素-I，一种临床相关但研究不足的分子，在牙周病中的作用，并 利用干扰素-β或干扰素-I为中心的炎症网络作为生物标志物进一步细化临床牙周 疾病分类。此外，这项研究提案将为将干扰素-IS作为辅助剂提供证据。 在一组患者中采取治疗措施，以改善精准的牙周健康。

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.