IL-22, Immune Plasticity, and Autotherapy in the Periodontium

IL-22、免疫可塑性和牙周组织自体疗法

• 批准号: 10116365
• 负责人: Georgios Hajishengallis
• 金额: $ 38.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116365
• 关键词: Address; Alveolar Bone Loss; Biological; Biological Process; Bone Regeneration; Cells; Chronic; Communication; Data; Disease; Economic Burden; Enzymes; Fibroblasts; Genes; Gingiva; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-17; Interleukins; Intervention; Intervention Studies; Lead; Mediating; Mesenchymal Differentiation; Mesenchymal Stem Cells; Microbe; Mitogen-Activated Protein Kinases; Mus; Natural regeneration; Nature; Oral; Osteogenesis; Pathogenesis; Patients; Periodontal Diseases; Periodontal Ligament; Periodontitis; Periodontium; Phase; Play; Public Health; Research; Resolution; Role; Series; Signal Transduction; Stat3 protein; Stress; Stromal Cells; System; Therapeutic; Tissue Preservation; Tissues; Tooth structure; biological systems; bone; bone loss; cytokine; design; dysbiosis; experimental study; fighting; host microbiome; immune function; immunoregulation; in vivo; inhibitor/antagonist; interleukin-22; microbial; microbiome alteration; novel; osteogenic; receptor; regenerative; repaired; response; stem cell function; synergism; therapeutic target; tissue regeneration; tissue repair

Project Summary Robustness is the ability of a system to maintain its functionality against internal or external perturbations and is enabled by mechanisms of plasticity, a major feature of biological systems such as the immune system. Autotherapies are approaches to optimize endogenous tissue responses to maintain health, treat diseases and enhance tissue repair, in great part by restoring biological robustness. Interleukin (IL)-22 mediates unidirectional communication from immune cells to tissue stromal cells and promotes homeostatic immunity, stem cell function and tissue regeneration. However, IL-22 is associated with both detrimental and protective activities in chronic inflammatory disorders, which has confounded its potential as a therapeutic target. The overall objective of this proposal is to clearly define the functions of IL-22 in periodontal disease (PD) and attain a context-dependent understanding of its protective or destructive potential, which will enable IL-22-targeted autotherapies to promote immune robustness in the periodontium. The overall hypothesis is that IL-22 acts in a context-dependent manner that influences the plasticity of the tissue from one tailored to perform immune surveillance or fight infections, to one fitted for regeneration. Specifically, IL-22 is proposed to regulate periodontal tissue immune plasticity by (i) preserving tissue integrity during steady-state (examined in Aim 1), contributing to vigorous immune responses that become destructive during PD (Aim 2), and acting as an effector of bone regeneration in the resolution phase (Aim 3). In Aim 1, in vivo intervention studies were designed to explore the requirement for IL-22 in periodontal tissue homeostasis at steady state. Aim 2 examines, through both in vitro and in vivo mechanistic experiments, the hypothesis that IL-22 synergizes with IL-17, a proinflammatory cytokine that is upregulated in PD, to promote destructive inflammation during the inductive phase of PD. Aim 3 explores the hypothesis that IL-22 promotes inflammation clearance and bone regeneration during the resolution phase of PD, when the expression of IL-17 massively declines. Regarding the mechanism by which IL-22 can promote osteogenesis, it will be investigated whether IL-22 promotes the proliferation and osteogenic differentiation of mesenchymal stem cells. The proposed studies are expected to lead to a context-dependent understanding of the biological functions of IL-22 in PD, leading to novel IL-22-targeted autotherapies to appropriately modulate immune plasticity and restore homeostasis in the periodontium, thereby benefiting PD patients.

项目摘要 鲁棒性是指系统在内部或外部扰动下保持其功能的能力， 可塑性机制是免疫系统等生物系统的主要特征。 自体疗法是优化内源性组织反应以维持健康、治疗疾病和预防疾病的方法。 增强组织修复，在很大程度上通过恢复生物鲁棒性。白细胞介素（IL）-22介导单向 从免疫细胞到组织基质细胞的通讯，并促进稳态免疫，干细胞功能 和组织再生。然而，IL-22与慢性炎症中的有害和保护活性相关。 炎症性疾病，这混淆了其作为治疗靶点的潜力。本报告的总体目标 建议是明确定义IL-22在牙周病（PD）中的功能，并获得上下文依赖性 了解其保护性或破坏性潜力，这将使IL-22靶向自身疗法能够促进 牙周组织中的免疫稳健性。总体假设是IL-22以上下文依赖的方式起作用。 影响组织可塑性的因素，从一个专门用于执行免疫监视或对抗感染的组织， 一个适合再生。具体而言，IL-22被提出通过以下方式调节牙周组织免疫可塑性：（i） 在稳定状态下保持组织完整性（在目标1中检查），有助于强有力的免疫应答 在PD期间变得具有破坏性（目的2），并在消退中作为骨再生的效应物 阶段（目标3）。在目的1中，设计了体内干预研究以探索在人乳腺癌中对IL-22的需求。 牙周组织稳态。目的2通过体外和体内两方面的机制， 实验中，假设IL-22与IL-17协同作用，IL-17是一种促炎细胞因子， PD，在PD的诱导阶段促进破坏性炎症。目标3探讨了假设， IL-22在PD消退期促进炎症清除和骨再生， IL-17的表达大幅下降。关于IL-22促进骨生成的机制， 将研究IL-22是否促进间充质干细胞的增殖和成骨分化 细胞拟议的研究预计将导致对生物学背景的理解 IL-22在PD中的功能，导致新的IL-22靶向自身疗法，以适当地调节免疫 可塑性和恢复牙周组织的稳态，从而使PD患者受益。