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: 10369593
• 负责人: Georgios Hajishengallis
• 金额: $ 38.21万
• 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/10369593
• 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; 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.

项目总结