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 鲁棒性是系统对内部或外部扰动保持其功能的能力，并且是 由可塑性机理启用，这是生物系统（例如免疫系统）的主要特征。 自动疗法是优化内源性组织反应以维持健康，治疗疾病和 通过恢复生物鲁棒性，可以在很大程度上增强组织修复。白介素（IL）-22介导单向 从免疫细胞到组织基质细胞的通信，并促进稳态免疫，干细胞功能 和组织再生。但是，IL-22与慢性的有害和保护活动有关 炎症性疾病已经混淆了其作为治疗靶点的潜力。总体目标 提案是要清楚地定义IL-22在牙周疾病（PD）中的功能，并达到上下文依赖性 了解其保护性或破坏性潜力，这将使IL-22靶向的自动疗法能够促进 牙周的免疫鲁棒性。总体假设是IL-22以上下文的方式起作用 这会影响组织的可塑性，从一个量身定制到进行免疫监视或对抗感染，到 一个适合再生。具体而言，提出IL-22来调节（i）调节牙周组织免疫可塑性 在稳态期间保留组织完整性（在AIM 1中检查），有助于剧烈的免疫反应 在PD期间（AIM 2）变得具有破坏性，并在分辨率中充当骨骼再生的效果。 阶段（目标3）。在AIM 1中，设计了体内干预研究以探索IL-22的要求 牙周组织稳态处于稳定状态。 AIM 2通过体外和体内机械进行检查 实验，即IL-22与IL-17协同作用的假设，IL-17是一种促炎细胞因子，在 PD，以促进PD电感阶段的破坏性炎症。 AIM 3探讨了以下假设 IL-22在PD的分辨率阶段促进炎症清除率和骨再生，当时 IL-17的表达急剧下降。关于IL-22可以促进成骨的机制， 将研究IL-22是否促进间充质茎的增殖和成骨分化 细胞。预计拟议的研究将导致对生物学的上下文依赖性理解 IL-22在PD中的功能，导致新颖的IL-22靶向自动疗法适当调节免疫 牙周地区的可塑性和恢复体内平衡，从而使PD患者受益。