Aging and IL-7 mediated CD8+ T cell survival
衰老和 IL-7 介导的 CD8 T 细胞存活
基本信息
- 批准号:10207438
- 负责人:
- 金额:$ 36.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAddressAffectAgeAgingAllogenicBiologicalBiological AssayCD8-Positive T-LymphocytesCX3C ChemokinesCell Culture TechniquesCell SurvivalCellsChemotaxisCollaborationsCytomegalovirusCytomegalovirus InfectionsDNADNA MethylationDNA Methylation RegulationDevelopmentElderlyEndothelial CellsFractalkineGene ExpressionGene Expression RegulationGenesGoalsHumanIL7 geneIL7R geneImmuneImmune responseImmune systemImmunityImplantInfectionInflammagingInflammationInflammatoryInflammatory ResponseInterferonsInterleukin 7 ReceptorInterleukin-15Interleukin-6LengthLightMaintenanceMalignant NeoplasmsMediatingMemoryMusPathway interactionsPeripheral Blood Mononuclear CellPopulationProcessProductionPublishingRecording of previous eventsRegulationRegulator GenesRoleSecondary toSerologySignal PathwaySiteT cell responseT-Cell DevelopmentT-LymphocyteTNF geneTestingUp-Regulationage effectbasechemokinechemokine receptorcytokinecytotoxicfractalkine receptorgenome-widehealthy aginghumanized mouseinterestperforinperipheral bloodpromoterresponsetelomeretissue injurytraittranscription factoryoung adult
项目摘要
Project Summary/Abstract: Alterations in the immune system occur with aging, likely contributing to the
development of infections and malignancies. Although the latter finding suggests an age-associated decline of
the immune system, aging could be regarded as a condition with dysregulated inflammation (inflammaging). In
T cell immunity, probably, the most prominent change with aging is the expansion of memory CD8+ T cells in
peripheral blood although its exact mechanism(s) and significance are yet to be determined. My lab
investigated whether the expansion of human memory CD8+ T cells with aging was secondary to increased
expression of IL-7 receptor alpha chain (IL-7Rα) which dictates the response to the pro-survival cytokine IL-7.
We found two cell populations which expressed low and high levels of IL-7Rα (IL-7Rαlow and high) in effector
memory (EM) CD8+ T cells in peripheral blood. Of interest, older adults (OA, age ≥ 65) had expansion of IL-
7Rαlow EM CD8+ T cells (up to 70% of total CD8+ T cells), which are largely cytotoxic and inflammatory cytokine
producing cells, compared to young adults (YA, age ≤ 40). Such cell expansion is associated with
cytomegalovirus infection, which persists for lifetime, as well as with enhanced production of and proliferative
response to IL-15 that promotes the maintenance and effector function of memory CD8+ T cells. However, the
significance of the expansion of IL-7Rαlow EM CD8+ T cells in OA remains largely unknown, especially in the
context of inflammation. To address this critical question, we performed a genome-wide DNA methylation
analysis in IL-7Rαlow and high EM CD8+ T cells since DNA methylation modulates gene expression. IL-7Rαlow
EM CD8+ T cells have hypomethylation of DNA in a group of chemotaxis-associated genes, including CX3CR1
(receptor for fractalkine), with enhanced expression. Plus, we noticed increased CX3CR1 expression by IL-
7Rαlow EM CD8+ T cells in OA compared to YA as well as the effect of aging on DNA methylation of the
CX3CR1 promoter in the same cells. Thus, we hypothesize that aging “qualitatively” enhances the pro-
inflammatory traits of human IL-7Rαlow EM CD8+ T cells by affecting gene regulatory mechanisms, including
DNA methylation and IL-15-mediated responses in addition to expanding them and that soluble factors
produced from such cells promote inflammation by activating other cells. This hypothesis will be tested with:
Aim 1. Investigate whether aging promotes IL-7Rαlow EM CD8+ T cell-mediated inflammatory response in
humans by altering inflammatory gene regulation via DNA methylation and transcription factors; Aim 2.
Elucidate age-associated alterations in IL-15-mediated inflammatory response in human IL-7Rαlow EM CD8+ T
cells; and Aim 3. Investigate the significance of age-associated alterations of IL-7Rαlow EM CD8+ T cells in
promoting inflammatory responses using ex vivo bioassay and humanized mice. Our results will shed light on
the biological significance of expanded memory CD8+ T cells with aging, especially in the aspect of
inflammation, as well as on the possible role of gene regulations in promoting this process.
项目摘要/摘要:随着年龄的增长,免疫系统会发生变化,这可能会导致
感染和恶性肿瘤的发展。尽管后一项发现表明,与年龄相关的
免疫系统的老化可以被认为是一种炎症(炎症)失调的状态。在……里面
T细胞免疫,随着年龄的增长,最显著的变化可能是记忆中CD8+T细胞的扩张
外周血的确切作用机制(S)和意义尚不清楚。我的实验室
研究了人类记忆CD8+T细胞随年龄增长的扩增是否继发于增龄
IL-7受体α链(IL-7Rα)的表达,它决定了对促生存细胞因子IL-7的反应。
我们在效应器中发现了低水平和高水平表达IL-7Rα(IL-7Rα低水平和高水平)的两个细胞群
外周血中的记忆(EM)CD8+T细胞。有趣的是,老年人(OA,65岁,≥)有IL-2的扩张。
7Rα低EMCD8+T细胞(高达总CD8+T细胞的70%),主要是细胞毒和炎性细胞因子
产生细胞,与年轻人(YA,年龄≤40岁)相比。这种单元格扩展与
巨细胞病毒感染,这种感染持续终生,并伴随着增加的产量和增殖性
对IL-15的反应,促进记忆CD8+T细胞的维持和效应功能。然而,
IL-7Rα低EMCD8+T细胞在骨性关节炎中的意义尚不清楚,尤其是在骨性关节炎
炎症的背景。为了解决这个关键问题,我们进行了全基因组DNA甲基化
IL-7Rα低、高EMCD8+T细胞甲基化调控基因表达的分析IL-7Rα低电平
EM CD8+T细胞存在包括CX3CR1在内的一组趋化相关基因的DNA低甲基化
(Fractalkine受体),表达增强。此外,我们注意到IL-1增加了CX3CR1的表达。
7Rα低EMCD8+T细胞在骨性关节炎和慢性再生障碍性关节炎中的比较及增龄对其甲基化的影响
CX3CR1启动子在同一细胞中。因此,我们假设衰老在质量上增强了人的健康。
影响基因调控机制的人IL-7Rα低EMCD8+T细胞炎症特性
DNA甲基化和IL-15介导的反应以及它们和可溶性因子
由这种细胞产生的物质通过激活其他细胞来促进炎症。这一假设将通过以下几个方面进行验证:
目的1.探讨增龄是否促进IL-7Rα低EMCD8+T细胞介导的炎症反应
人类通过DNA甲基化和转录因子改变炎症基因调控;目标2。
人IL-7Rα低EMCD8+T细胞IL-15介导的炎症反应的增龄变化
目的3.探讨IL-7Rα低EMCD8+T细胞增龄变化的意义
使用体外生物测定和人源化小鼠促进炎症反应。我们的结果将为我们提供
扩增记忆CD8+T细胞在增龄过程中的生物学意义
炎症,以及基因调控在促进这一过程中可能发挥的作用。
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 }}
Insoo Kang其他文献
Insoo Kang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('Insoo Kang', 18)}}的其他基金
Investigating monocyte activation pathways in lupus
研究狼疮中的单核细胞激活途径
- 批准号:
10731104 - 财政年份:2023
- 资助金额:
$ 36.85万 - 项目类别:
Studying alterations of T cell immune responses in the 17q12 deletion syndrome
研究 17q12 缺失综合征中 T 细胞免疫反应的变化
- 批准号:
10518405 - 财政年份:2021
- 资助金额:
$ 36.85万 - 项目类别:
Studying alterations of T cell immune responses in the 17q12 deletion syndrome
研究 17q12 缺失综合征中 T 细胞免疫反应的变化
- 批准号:
10391990 - 财政年份:2021
- 资助金额:
$ 36.85万 - 项目类别:
Studying the impact of altered CD8+ T cell immunity in Alzheimer's disease
研究 CD8 T 细胞免疫改变对阿尔茨海默病的影响
- 批准号:
10119925 - 财政年份:2018
- 资助金额:
$ 36.85万 - 项目类别:
Aging and IL-7 mediated CD8+ T cell survival
衰老和 IL-7 介导的 CD8 T 细胞存活
- 批准号:
10443824 - 财政年份:2018
- 资助金额:
$ 36.85万 - 项目类别:
Aging and IL-7 mediated CD8+ T cell survival
衰老和 IL-7 介导的 CD8 T 细胞存活
- 批准号:
9764233 - 财政年份:2018
- 资助金额:
$ 36.85万 - 项目类别:
The Impact of Aging and HIV Infection on Immunologic and Transcriptomic Signatures of Influenza Vaccine Response
衰老和 HIV 感染对流感疫苗反应的免疫学和转录组学特征的影响
- 批准号:
10183118 - 财政年份:2017
- 资助金额:
$ 36.85万 - 项目类别:
Studying the effects of vitamin D on FOXP3 and IL-17 expression in human CD4+ T c
研究维生素 D 对人 CD4 T c 中 FOXP3 和 IL-17 表达的影响
- 批准号:
7938575 - 财政年份:2009
- 资助金额:
$ 36.85万 - 项目类别:
Studying the effects of vitamin D on FOXP3 and IL-17 expression in human CD4+ T c
研究维生素 D 对人 CD4 T c 中 FOXP3 和 IL-17 表达的影响
- 批准号:
7706357 - 财政年份:2009
- 资助金额:
$ 36.85万 - 项目类别:
Lymphoid neogenesis and CD4+T cell differentiation in primary Sjogren's syndrome
原发性干燥综合征中的淋巴新生和 CD4 T 细胞分化
- 批准号:
7687681 - 财政年份:2009
- 资助金额:
$ 36.85万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 36.85万 - 项目类别:
Research Grant