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
基本信息
- 批准号:10551226
- 负责人:
- 金额:$ 37.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectArthritisBone MarrowBone Marrow CellsBone Marrow TransplantationCardiovascular DiseasesCell SeparationCellsCellular AssayChromatinChronicChronic DiseaseDataDevelopmentDiseaseEpidemiologyEpigenetic ProcessFutureGene ExpressionHematopoietic stem cellsImmuneImmunologic MemoryInfectionInflammationInflammatoryInflammatory ArthritisInterleukin-1 ReceptorsInterleukin-1 betaInvestigationKnowledgeLeukocytesLigatureLong-Term EffectsMediatingMemoryModificationMusMyelogenousMyeloid CellsMyelopoiesisNatural ImmunityNon-Insulin-Dependent Diabetes MellitusOralPTPRC genePeriodontal DiseasesPeriodontitisPeripheralPhenotypePre-Clinical ModelPredispositionProceduresProductionProliferatingReadinessRheumatoid ArthritisRoleSeminalSignal TransductionStimulusStudy modelsSystemSystemic diseaseTamoxifenTestingTrainingTransplantationTransposasechronic inflammatory diseasecollagen antibody induced arthritiscomorbiditycongeniccytokinedesignexperimental studyholistic approachinflammatory bone lossinsightnovelnovel therapeutic interventionpharmacologicprogenitorstem cellssystemic inflammatory responsetherapeutic targettranscriptomicstransmission process
项目摘要
Project Summary
Periodontal disease (PD) is a prevalent oral inflammatory condition that is epidemiologically associated with
systemic disorders (comorbidities), such as, cardiovascular disease, rheumatoid arthritis, and type-2 diabetes.
An independent association between PD and comorbidities remains even after adjustment for confounders. A
possible factor contributing to this independent association is that PD can cause low-grade systemic
inflammation, which may in turn influence comorbidities. The relationship between PD and systemic comorbidities
is bidirectional in that systemic diseases can also promote susceptibility to PD. However, there is no known
unifying causal mechanism that can explain how PD affects and is affected by comorbidities. To mechanistically
explain the reciprocal association between PD and comorbid conditions, a novel hypothesis is proposed based
on the recent concept that systemic inflammatory stimuli can cause epigenetic rewiring of hematopoietic stem
and progenitor cells (HSPCs) in the bone marrow, which enables these cells to give rise to ‘trained’ myeloid cells
that can respond more strongly to future stimuli. This concept represents a form of innate immune memory and
is known as ‘trained innate immunity’ (TII). TII can be protective in infections but potentially detrimental, hence
maladaptive, in inflammatory disorders. Thus, given that chronic inflammatory diseases are – in large part –
driven by the action of inflammatory myeloid cells, inflammation-driven transcriptomic and epigenetic alterations
in their bone marrow progenitors are likely to influence the initiation or the progression of different chronic
inflammatory disorders that emerge as comorbidities. This project involves investigation of the comorbidity of PD
with another inflammatory bone loss disorder, rheumatoid arthritis. The overarching hypothesis is that
maladaptive TII constitutes a mechanistic basis for the comorbid connection of PD and arthritis, which are studied
using validated preclinical models, ligature-induced PD (LIP) and collagen antibody-induced arthritis (CAIA),
respectively. The objective of Aim 1 is to show that inflammation-adapted HSPCs in the bone marrow mediates
the comorbid association of PD and inflammatory arthritis. That the proposed maladaptive effect is mediated by
inflammation-adapted (‘trained’) HSPCs will be tested by bone marrow transplantation experiments. Aim 2 was
designed to investigate whether experimental PD induces transmissible epigenetic modifications in bone marrow
progenitors towards a maladaptive inflammatory phenotype that underlies the development of inflammatory
comorbidities. Further studies are proposed to show that interleukin-1β acts on HSPCs to mediate LIP-induced
trained myelopoiesis and increased disease activity (Aim 3). If successful, this project will provide a unifying
network for and mechanistic insights into the interconnection of inflammatory comorbidities and maladaptive TII
in the bone marrow. Such conceptual framework could also provide a platform for novel therapeutic interventions
targeting inflammatory comorbidities via pharmacological modulation of TII.
项目总结
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:
$ 37.38万 - 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:
$ 37.38万 - 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:
$ 37.38万 - 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:
$ 37.38万 - 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:
$ 37.38万 - 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:
$ 37.38万 - 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:
$ 37.38万 - 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:
$ 37.38万 - 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:
9160246 - 财政年份:2016
- 资助金额:
$ 37.38万 - 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:
$ 37.38万 - 项目类别:
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