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:10328655
- 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 DiseasesCellsCellular AssayChromatinChronicChronic DiseaseDataDevelopmentDiseaseEpidemiologyEpigenetic ProcessFutureGene ExpressionHematopoietic stem cellsImmuneImmunologic MemoryInfectionInflammationInflammatoryInflammatory ArthritisInterleukin-1 ReceptorsInterleukin-1 betaInvestigationKnowledgeLeukocytesLigatureLong-Term EffectsMediatingMemoryModificationMusMyelogenousMyeloid CellsMyelopoiesisNatural ImmunityNon-Insulin-Dependent Diabetes MellitusOralPTPRC genePeriodontal DiseasesPeriodontitisPeripheralPharmacologyPhenotypePre-Clinical ModelPredispositionProceduresProductionReadinessRheumatoid ArthritisRoleSeminalSignal TransductionStimulusStudy SectionStudy modelsSystemSystemic diseaseTamoxifenTestingTrainingTransplantationTransposasebasechronic inflammatory diseasecollagen antibody induced arthritiscomorbiditycongeniccytokinedesignexperimental studyholistic approachinflammatory bone lossinsightnovelnovel therapeutic interventionprogenitorstem cellssystemic inflammatory responsetherapeutic targettranscriptomics
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症性疾病,在流行病学上与
系统性疾病(合并症),如心血管疾病、类风湿性关节炎和2型糖尿病。
即使在对混杂因素进行调整后,帕金森病和合并症之间的独立关联仍然存在。一个
导致这种独立关联的可能因素是帕金森病可导致低度系统性
炎症,这可能反过来影响合并症。帕金森病与全身合并症的关系
是双向的,因为系统性疾病也会增加帕金森病的易感性。然而,目前尚不清楚
统一的因果机制,可以解释帕金森病如何影响和受到共病的影响。机械地
解释帕金森病和并存情况之间的相互关联,提出了一个新的假设,基于
关于全身性炎症刺激可导致造血干细胞表观遗传重排的最新概念
和骨髓中的祖细胞(HSPC),这使这些细胞能够产生“经过训练的”髓系细胞
可以对未来的刺激做出更强烈的反应。这一概念代表了一种先天免疫记忆,
被称为“训练有素的先天免疫”(TII)。TiI可以在感染中起到保护作用,但可能是有害的,因此
适应不良,炎症性疾病。因此,鉴于慢性炎症性疾病--很大程度上--
在炎性髓系细胞的作用下,炎症驱动的转录和表观遗传学改变
在他们的骨髓祖细胞可能会影响不同慢性疾病的发生或发展
以合并症形式出现的炎症性疾病。该项目涉及帕金森病共病的调查。
患有另一种炎症性骨丢失障碍,类风湿性关节炎。最重要的假设是
不适应的TII构成了帕金森病和关节炎共病联系的机制基础,我们对此进行了研究
使用经过验证的临床前模型,结扎诱导的PD(LIP)和胶原抗体诱导的关节炎(CAIA),
分别进行了分析。目标1的目的是显示骨髓中炎症适应的HSPC介导
帕金森病与炎症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来测试炎症适应的(‘训练的’)HSPC。目标2是
旨在研究实验性帕金森病是否会导致骨髓中可传递的表观遗传修饰
导致炎症发展的不适应性炎症表型的祖细胞
合并症。进一步的研究表明,白介素1β作用于HSPC,介导嘴唇诱导
训练骨髓生成和增加疾病活跃度(目标3)。如果成功,这个项目将提供一个统一的
炎症性并存和适应不良TII相互联系的网络和机制洞察力
在骨髓中。这种概念性框架还可以为新的治疗干预提供平台
通过对TII的药理调节来靶向炎性合并症。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Georgios Hajishengallis其他文献
Georgios Hajishengallis的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10551226 - 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:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 37.38万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 37.38万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 37.38万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 37.38万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 37.38万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 37.38万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 37.38万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 37.38万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 37.38万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 37.38万 - 项目类别:
Grant-in-Aid for Early-Career Scientists