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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要鲁棒性是指系统针对内部或外部扰动维持其功能的能力，由可塑性机制实现，可塑性是免疫系统等生物系统的一个主要特征。自体疗法是优化内源性组织反应以维持健康、治疗疾病和增强组织修复，很大程度上是通过恢复生物稳健性来实现的。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，促进稳态免疫、干细胞功能和组织再生。然而，IL-22 与慢性疾病的有害和保护活性相关。炎症性疾病，这削弱了其作为治疗靶点的潜力。本次活动的总体目标该提案的目的是明确定义 IL-22 在牙周病 (PD) 中的功能，并获得上下文相关的结果了解其保护或破坏潜力，这将使靶向 IL-22 的自我疗法能够促进牙周组织的免疫稳健性。总体假设是 IL-22 以上下文依赖性方式发挥作用影响组织的可塑性，从专门用于执行免疫监视或对抗感染的组织，到一个安装用于再生。具体而言，IL-22 被提议通过以下方式调节牙周组织免疫可塑性：在稳态期间保持组织完整性（在目标 1 中进行检查），有助于产生旺盛的免疫反应在 PD 期间变得具有破坏性（目标 2），并在解决方案中充当骨再生的效应器阶段（目标 3）。在目标 1 中，体内干预研究旨在探索体内对 IL-22 的需求。牙周组织稳态处于稳态。目标 2 通过体外和体内机制检查实验中，假设 IL-22 与 IL-17 具有协同作用，IL-17 是一种促炎细胞因子，在 PD，在 PD 诱导阶段促进破坏性炎症。目标 3 探讨了以下假设： IL-22 在 PD 消退阶段促进炎症清除和骨再生，此时 IL-17 的表达大幅下降。关于IL-22促进成骨的机制，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的上下文依赖的理解 IL-22 在 PD 中的功能，导致新型 IL-22 靶向自体疗法能够适当调节免疫牙周组织的可塑性并恢复稳态，从而使PD患者受益。