Local endogenous regulators of functional immune plasticity in the periodontium

牙周组织功能性免疫可塑性的局部内源性调节因子

• 批准号: 10415785
• 负责人: Georgios Hajishengallis
• 金额: $ 35.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415785
• 关键词: Address; Affect; Alveolar Bone Loss; Animal Model; Anti-Inflammatory Agents; Area; BCL6 gene; Biology; Cells; Collaborations; Data; Development; Disease; Dissection; Down-Regulation; Endothelial Cells; Endothelium; Fibroblasts; Gatekeeping; Generations; Genetic Transcription; Germany; Health; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Inflammation; Inflammatory; Integrins; Interleukin-1 beta; Interleukin-17; Intervention Studies; Location; Lymphocyte; Maintenance; Modeling; Molecular; Mouth Diseases; Multiple Sclerosis; Mus; Nature; Neuraxis; Paper; Pathogenesis; Pennsylvania; Periodontal Diseases; Periodontitis; Periodontium; Phenotype; Production; Proteins; Psychiatry; Publications; Regulation; Research; Resolution; Science; Signal Transduction; Source; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Tooth structure; Transcription Repressor; Universities; Up-Regulation; Wild Type Mouse; base; bone loss; cytokine; functional plasticity; immune function; immune system function; inflammatory bone loss; innovation; insight; interleukin-23; macrophage; mouse model; novel; overexpression; pre-clinical; prototype; reconstitution; recruit; restoration; γδ T cells

Project Summary Periodontitis is a prevalent inflammatory disease that causes destruction of the tooth-supporting tissues (periodontium). The maintenance of homeostatic mechanisms is essential for protection against inflammatory damage in the periodontium. In this context, the function of immune cells needs to be tailored according to specific environmental challenges; for instance, the ability to mount a robust immune response needs to be followed by timely resolution of inflammation and restoration of tissue integrity. This adaptation is known as functional immune plasticity and results from an intimate crosstalk of immune cells with tissue-derived factors, which, in turn, are regulated by and reflect changes of the tissue microenvironment. The functional characterization of a novel endogenous homeostatic molecule, derived from periodontal tissue-resident cells and designated developmental endothelial locus-1 (Del-1), has significantly contributed as a prototype paradigm to the emerging concept that tissues have a “regulatory say” over the host immune response. This project investigates the overarching hypothesis that Del-1 acts as a local endogenous regulator of functional immune plasticity by not only regulating periodontal inflammation but also by promoting resolution thereof, and hence periodontal homeostasis. The proposal comprises three specific aims and focuses on relevant animal model-based mechanistic and intervention studies, including mice with lineage-specific deletions or overexpression of Del-1. In Aim 1, it is proposed that Del-1 promotes the resolution of periodontal inflammation. Aim 2 investigates the mechanism(s) by which Del-1 promotes homeostatic immunity. Specifically, it is proposed that Del-1 modulates macrophage plasticity via two complementary mechanisms; inhibition of inflammatory signaling and promotion of a pro-resolution reprogramming of macrophages, both of which may impact the function of other immune cells, such as T cells. Aim 3 is to determine the importance of the location of Del-1 expression in the regulation of periodontal inflammation and bone loss. The concept to establish here is that the cellular source and location of homeostatic molecule expression is functionally important in that it allows it to perform distinct functions in an appropriate context. This application therefore offers a fundamentally new insight into the local mechanisms that govern and tailor the function of the immune system. The proposed research is likely to reveal hitherto unknown mechanisms of immune system plasticity relevant to the pathogenesis of oral diseases; these mechanisms can be harnessed to develop innovative approaches to inhibit destructive inflammation and restore tissue integrity.

项目摘要 牙周炎是一种常见的炎症性疾病，会破坏牙齿的支持组织。 (牙周组织)。维持体内平衡机制是预防炎症的关键。 牙周组织受损。在这种情况下，免疫细胞的功能需要根据 特定的环境挑战；例如，建立强大免疫反应的能力需要 其次是及时消退炎症和恢复组织完整性。这种适应被称为 功能免疫可塑性和免疫细胞与组织衍生因子的亲密串扰的结果， 它们反过来又受组织微环境的调节并反映其变化。功能界别 牙周组织驻留细胞来源的新型内源性动态平衡分子的特性 并被命名为发育内皮基因座-1(Del-1)，作为一个原型做出了重大贡献 组织对宿主免疫反应有“调控发言权”这一新兴概念的范例。这 该项目调查了Del-1作为功能性局部内源性调节因子的总体假设 免疫可塑性，不仅通过调节牙周炎症，而且通过促进其消退，以及 因此，牙周动态平衡。该提案包括三个具体目标，并侧重于相关动物 基于模型的机制和干预研究，包括具有特定血统缺失或 Del-1基因的过表达。目的1提出Del-1促进牙周组织溶解 发炎。目的2探讨DEL-1促进体内平衡免疫的机制(S)。 具体地说，Del-1通过两种互补的机制调节巨噬细胞的可塑性； 抑制炎症信号和促进巨噬细胞分解前重编程，两者均 这可能会影响其他免疫细胞的功能，如T细胞。目标3是确定 Del-1表达在牙周炎和骨丢失调节中的定位概念是为了 这里确定的是，动态平衡分子表达的细胞来源和位置在功能上是 重要的是，它允许它在适当的上下文中执行不同的功能。因此，此应用程序 为管理和调整免疫功能的局部机制提供了一个全新的见解 系统。这项拟议中的研究可能会揭示迄今未知的免疫系统可塑性机制 与口腔疾病的发病机制相关；这些机制可以被利用来开发创新的 抑制破坏性炎症和恢复组织完整性的方法。