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.
项目摘要
牙周病(PD)是一种流行的口腔炎性疾病,在流行病学上与
全身性疾病(合并症),如心血管疾病、类风湿性关节炎和2型糖尿病。
即使在调整混杂因素后,PD和合并症之间的独立关联仍然存在。一
导致这种独立关联的可能因素是PD可引起低级别的全身性
炎症,这反过来可能影响合并症。PD与全身性合并症的关系
是双向的,全身性疾病也可以促进对PD的易感性。然而,没有已知的
统一的因果机制,可以解释PD如何影响和受合并症的影响。机械地
解释PD和共病条件之间的相互关联,提出了一种新的假设,
关于系统性炎症刺激可引起造血干细胞表观遗传重连的最新概念,
和骨髓中的祖细胞(HSPCs),这使得这些细胞能够产生“训练”的骨髓细胞
能够对未来的刺激做出更强烈的反应。这个概念代表了一种先天免疫记忆的形式,
被称为“训练的先天免疫”(TII)。TII可以在感染中起保护作用,但可能有害,因此
适应不良,炎症性疾病。因此,鉴于慢性炎症性疾病-在很大程度上-
由炎性骨髓细胞的作用驱动,炎症驱动的转录组和表观遗传改变
在他们的骨髓祖细胞可能会影响不同的慢性疾病的开始或进展,
作为合并症出现的炎性疾病。本课题主要研究帕金森病的合并症,
另一种炎症性骨质流失疾病类风湿性关节炎首要假设是,
适应不良的TII构成了PD和关节炎共病联系的机制基础,
使用经验证的临床前模型,结扎诱导的PD(LIP)和胶原抗体诱导的关节炎(CAIA),
分别目的1的目的是显示骨髓中的炎症适应性HSPCs介导
帕金森病和炎性关节炎的共病关系。所提出的适应不良效应是由
将通过骨髓移植实验测试炎症适应的(“训练的”)HSPC。目标2是
旨在研究实验性PD是否诱导骨髓中的可传播表观遗传修饰
祖细胞向适应不良的炎性表型发展,
合并症。进一步的研究表明,白细胞介素-1 β作用于HSPCs,介导LPS诱导的HSPCs凋亡。
训练的骨髓生成和增加的疾病活动性(目的3)。如果成功,该项目将提供一个统一的
炎症共病和适应不良TII相互联系的网络和机制见解
在骨髓里。这种概念框架也可以为新的治疗干预提供平台
通过TII的药理学调节靶向炎性共病。
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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