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
基本信息
- 批准号:9160246
- 负责人:
- 金额:$ 36.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlveolar Bone LossAnimal ModelAnti-Inflammatory AgentsAnti-inflammatoryAreaBCL6 geneBiologyCellsCollaborationsDataDevelopmentDiseaseDissectionDown-RegulationEndothelial CellsFibroblastsGatekeepingGenerationsGermanyHealthHomeostasisHumanImmuneImmune responseImmune systemImmunityInflammationInflammatoryIntegrinsInterleukin-1 betaInterleukin-17Intervention StudiesLocationLymphocyteMaintenanceModelingMolecularMouth DiseasesMultiple SclerosisMusNatureNeuraxisPaperPathogenesisPennsylvaniaPeriodontal DiseasesPeriodontitisPeriodontiumProductionProteinsPsychiatryPublicationsRecruitment ActivityRegulationResearchResolutionScienceSignal TransductionSourceT-LymphocyteTestingTherapeuticTissuesTooth structureTranscription Repressor/CorepressorUniversitiesUp-RegulationWild Type Mousebasebone losschromosome 1 losscytokinefunctional plasticityimmune functioninflammatory bone lossinnovationinsightinterleukin-23macrophagemouse modelnoveloverexpressionpre-clinicalprototypereconstitutionrestoration
项目摘要
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,可导致牙齿支持组织的破坏
(牙周组织)。维持体内平衡机制对于防止炎症反应是必不可少的。
牙周组织损伤在这种情况下,免疫细胞的功能需要根据
具体的环境挑战;例如,需要建立强大的免疫反应的能力,
随后及时解决炎症并恢复组织完整性。这种适应被称为
功能性免疫可塑性和结果从一个密切的串扰免疫细胞与组织衍生的因素,
其又受组织微环境的变化调节并反映组织微环境的变化。功能
牙周组织驻留细胞来源的一种新的内源性稳态分子的鉴定
命名为发育内皮基因座-1(Del-1),作为一个原型,
这是一个新概念的范例,即组织对宿主免疫反应具有“调节性发言权”。这
该项目研究了Del-1作为功能性的局部内源性调节剂的总体假设。
通过不仅调节牙周炎症而且促进其消退的免疫可塑性,和
因此牙周内环境稳定。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,包括具有谱系特异性缺失的小鼠,或
Del-1的过度表达。在目的1中,提出Del-1促进牙周炎的消退,
炎症目的2研究Del-1促进稳态免疫的机制。
特别地,提出Del-1通过两种互补机制调节巨噬细胞可塑性;
抑制炎症信号传导和促进巨噬细胞的促消退重编程,
这可能会影响其他免疫细胞的功能,如T细胞。目标3是确定以下方面的重要性:
Del-1在牙周炎和骨丢失调控中的定位。概念到
这里确定的是,稳态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,本申请
提供了一个从根本上新的洞察到当地的机制,管理和定制的免疫功能,
系统这项拟议中的研究可能会揭示迄今为止未知的免疫系统可塑性机制
与口腔疾病的发病机制有关;这些机制可以用来开发创新的
抑制破坏性炎症和恢复组织完整性的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Georgios Hajishengallis其他文献
Georgios Hajishengallis的其他文献
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{{ truncateString('Georgios Hajishengallis', 18)}}的其他基金
Trained innate immunity and periodontitis-associated comorbidities
训练有素的先天免疫和牙周炎相关合并症
- 批准号:
10328655 - 财政年份:2022
- 资助金额:
$ 36.48万 - 项目类别:
Trained innate immunity and periodontitis-associated comorbidities
训练有素的先天免疫和牙周炎相关合并症
- 批准号:
10551226 - 财政年份:2022
- 资助金额:
$ 36.48万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 36.48万 - 项目类别:
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:
10577869 - 财政年份:2020
- 资助金额:
$ 36.48万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 36.48万 - 项目类别:
Aging and dysfunction of progenitor niches: Role of Del-1
祖细胞生态位的衰老和功能障碍:Del-1 的作用
- 批准号:
10536596 - 财政年份:2020
- 资助金额:
$ 36.48万 - 项目类别:
Aging and dysfunction of progenitor niches: Role of Del-1
祖细胞生态位的衰老和功能障碍:Del-1 的作用
- 批准号:
10312010 - 财政年份:2020
- 资助金额:
$ 36.48万 - 项目类别:
Neutrophil homeostasis and periodontitis: Novel concepts and treatments
中性粒细胞稳态和牙周炎:新概念和治疗
- 批准号:
9357605 - 财政年份:2016
- 资助金额:
$ 36.48万 - 项目类别:
Neutrophil homeostasis and periodontitis: Novel concepts and treatments
中性粒细胞稳态和牙周炎:新概念和治疗
- 批准号:
9974997 - 财政年份:2016
- 资助金额:
$ 36.48万 - 项目类别:
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:
10449323 - 财政年份:2016
- 资助金额:
$ 36.48万 - 项目类别:
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