Role of IL-6 and IL-1b in immune dysfunction during aging, HIV, and HCV infection
IL-6 和 IL-1b 在衰老、HIV 和 HCV 感染期间免疫功能障碍中的作用
基本信息
- 批准号:10291768
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAgeAgingAmericanAntigensAntiviral TherapyCardiovascular DiseasesCaringCell AgingCell Culture TechniquesCell ProliferationCell SeparationCell physiologyCellsChronicChronic Hepatitis CCultured CellsDataDevelopmentElderlyExcisionExposure toFlow CytometryFunctional disorderGoalsHIVHIV InfectionsHIV/HCVHealthHepatitis CHepatitis C virusHomeostasisHumanIL6 geneIL7 geneImmuneImmune System DiseasesImmune systemImmunologic MarkersIn VitroIndividualInfectionInflammationInflammation MediatorsInflammatoryInterferonsInterleukin-1 betaInterleukin-6K-Series Research Career ProgramsLate EffectsLeftLiver diseasesLymphocytic choriomeningitis virusMalignant NeoplasmsMeasuresMorbidity - disease ratePatientsPeripheral Blood Mononuclear CellPhenotypePlasmaPopulationProductionProliferatingProteinsProviderRecoveryResearchResearch PersonnelRheumatoid ArthritisRoleSystemT-LymphocyteTestingTherapeuticTherapeutic InterventionUp-RegulationVeteransViralVirusVirus DiseasesVirus Replicationagedantiretroviral therapybasecareerchronic infectioncomorbiditycytokinedesignexhaustexhaustionhuman old age (65+)immune functionimmune healthimprovedinsightliver injurylymph nodesmilitary veteranmortalitymouse modelnovel strategiesolder patientpatient populationprogrammed cell death protein 1programsresponsesenescencesystemic inflammatory responsetargeted treatmenttherapeutic target
项目摘要
Chronic systemic inflammation is associated with immune dysfunction and morbidities in the elderly, treated
HIV infection, and HCV infection. We propose that circulating inflammatory proteins drive immune exhaustion
and senescence and contribute to the immune dysfunction seen in these patient groups. Nearly 4 million
Americans are infected with Hepatitis C Virus (HCV) and the mean age of US veterans infected with HCV is
nearing 65 years. Although the new IFN-free direct-acting antiviral therapy is highly effective at clearing virus
from patients, the patients are left with the consequences of decades of infection and liver damage, and it is
still unclear how long soluble mediators of inflammation persist, and how long immune dysfunction and
associated morbidity lasts. Similarly, even HIV-infected patients that have successfully controlled viral
replication with ART for decades have increased mortality and morbidity and persistent inflammation. The VA
is the largest single provider of HIV care in the US. Understanding what causes the continued morbidity in
these veteran patient populations is critical. The elderly, HCV and HIV-infected patients all have chronic
immune inflammation and these three patient groups share many of the same comorbidities including
cardiovascular disease, cancer, and liver disease. The project design of this CDA-2 application is based on the
understanding that patients with chronic viral infections and elderly patients show chronic elevated plasma
levels of IL-6, and our more recent data demonstrating elevated levels of IL-1β in lymph nodes of HIV-infected
patients. The central goals of this study are to determine the underlying mechanisms of IL-6 and IL-1β that
contribute to the development of immune exhaustion and senescence and to examine the potential therapeutic
role of temporarily blocking IL-6 and IL-1β during chronic infection to improve immune function and recovery of
exhausted or senescent T cells. The hypothesis that chronic elevated levels of IL-6 and IL-1β during aging,
HCV infection and HIV infection contribute to immune senescence and exhaustion and resulting immune
dysfunction will be tested in 3 specific Aims. Aim 1 will determine the phenotype and function of T cells that
have been exposed to IL-1β or IL-6 in vitro by sorting the cells positive for exhaustion or senescent markers
(PD-1, CD57, Tim-3, KLRG1, Lag3) and examining their functional abilities to determine if inflammatory
cytokines alone can drive senescence, independent of antigen exposure. Aim 2A will examine the expression
levels of exhaustion and senescent markers and the intracellular production of cytokines associated with the
senescence-associated secretory phenotype (SASP) in lymphocytess from HCV-infected, treated HIV-infected,
and elderly patients by flow cytometry. Aim 2B will examine the recovery and normalization of immune
function, longitudinally, in HIV-infected patients after initiation of ART and in HCV-infected patients after
initiation of IFN-free direct-acting antiviral therapy. In Aim 3 we will use a mouse model of chronic viral
infection (LCMV) to determine the effect of late blockade of IL-6 and IL-1β on the development of exhausted
and senescent T cells, and the recovery of T cell function and proliferative ability. The candidate's long term
goals are to understand the effects of chronic inflammation on health, the mechanisms by which the immune
system maintains homeostasis, and how inflammation disrupts the ability of the immune system to reestablish
homeostasis after infection and during aging. This focus supports a growing need nationwide to advance our
understanding and develop therapeutic strategies in the aging veteran population with and without chronic viral
infection. The candidate's career goals are to use this Career Development Award to successfully transition to
an independent investigator at the Louis Stokes Cleveland VAMC, and to establish a productive, thriving,
national leading research program in the VA system.
慢性全身性炎症与老年人的免疫功能障碍和发病率相关,
HIV感染和HCV感染。我们认为,循环炎症蛋白驱动免疫衰竭
和衰老,并导致这些患者组中观察到的免疫功能障碍。近4百万
美国人感染丙型肝炎病毒(HCV),感染HCV的美国退伍军人的平均年龄为
将近65岁。虽然新的无干扰素直接作用的抗病毒治疗在清除病毒方面非常有效,
从病人身上,病人留下了几十年的感染和肝损伤的后果,这是
目前还不清楚可溶性炎症介质持续多久,以及免疫功能障碍和
相关的发病率持续存在。同样,即使是成功控制病毒感染的艾滋病患者,
几十年来,ART的复制增加了死亡率和发病率以及持续性炎症。退伍军人管理局
是美国最大的艾滋病护理提供者。了解是什么原因导致持续的发病率,
这些退伍军人患者群体至关重要。老年人、HCV和HIV感染者都有慢性
免疫炎症,这三个患者组有许多相同的合并症,包括
心血管疾病、癌症和肝脏疾病。该CDA-2应用程序的项目设计基于
了解慢性病毒感染患者和老年患者显示慢性血浆浓度升高,
IL-6水平,以及我们最近的数据表明HIV感染者淋巴结中IL-1β水平升高。
患者本研究的中心目标是确定IL-6和IL-1β的潜在机制,
有助于免疫衰竭和衰老的发展,并检查潜在的治疗
暂时阻断IL-6和IL-1β在慢性感染中对改善免疫功能和恢复的作用
耗尽或衰老的T细胞。假设在衰老过程中IL-6和IL-1β水平慢性升高,
HCV感染和HIV感染导致免疫衰老和衰竭,
将在3个特定目标中测试功能障碍。目的1将确定T细胞的表型和功能,
通过分选衰竭或衰老标志物阳性的细胞,在体外暴露于IL-1β或IL-6
(PD-1,CD 57,Tim-3,KLRG 1,Lag 3),并检查它们的功能能力以确定是否存在炎性
细胞因子单独可以驱动衰老,而不依赖于抗原暴露。目标2A将检查表达式
衰竭和衰老标记物的水平以及与衰老相关的细胞因子的细胞内产生。
HCV感染者、经治疗的HIV感染者、
和老年患者。目的2B将检查免疫的恢复和正常化。
在HIV感染患者开始ART后和HCV感染患者开始ART后,
开始无干扰素的直接作用抗病毒治疗。在目标3中,我们将使用慢性病毒感染的小鼠模型,
感染(LCMV),以确定IL-6和IL-1β的晚期阻断对衰竭发展的影响。
和衰老T细胞,以及T细胞功能和增殖能力的恢复。候选人的长期
目标是了解慢性炎症对健康的影响,免疫系统的机制,
系统维持体内平衡,以及炎症如何破坏免疫系统重建的能力。
感染后和衰老期间的体内平衡。这一重点支持了全国范围内日益增长的需求,以推动我们的
了解和制定治疗策略,在老年退伍军人人口与非慢性病毒
感染候选人的职业目标是利用此职业发展奖成功过渡到
路易斯·斯托克斯·克利夫兰VAMC的独立调查员,并建立一个富有成效的,繁荣的,
全国领先的研究计划在VA系统。
项目成果
期刊论文数量(2)
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 }}
Carey Lynn Shive其他文献
Carey Lynn Shive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('Carey Lynn Shive', 18)}}的其他基金
Impact of preexisting immune profile in elderly on influenza vaccine response
老年人原有免疫特征对流感疫苗反应的影响
- 批准号:
10485431 - 财政年份:2022
- 资助金额:
-- - 项目类别:
COVID19: Respiratory SARS-CoV-2 seroprevalence and the association of humoral immune responses with clinical outcomes in veterans and employees in the Cleveland VA Medical Center
COVID19:克利夫兰退伍军人医疗中心退伍军人和员工的呼吸道 SARS-CoV-2 血清流行率以及体液免疫反应与临床结果的关联
- 批准号:
10160554 - 财政年份:2021
- 资助金额:
-- - 项目类别:
COVID19: Respiratory SARS-CoV-2 seroprevalence and the association of humoral immune responses with clinical outcomes in veterans and employees in the Cleveland VA Medical Center
COVID19:克利夫兰退伍军人医疗中心退伍军人和员工的呼吸道 SARS-CoV-2 血清流行率以及体液免疫反应与临床结果的关联
- 批准号:
10359116 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Role of IL-6 and IL-1b in immune dysfunction during aging, HIV, and HCV infection
IL-6 和 IL-1b 在衰老、HIV 和 HCV 感染期间免疫功能障碍中的作用
- 批准号:
9858239 - 财政年份:2017
- 资助金额:
-- - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
The Phenomenon of Stem Cell Aging according to Methylation Estimates of Age After Hematopoietic Stem Cell Transplantation
根据造血干细胞移植后甲基化年龄估算干细胞衰老现象
- 批准号:
23K07844 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of Age-dependent Functional Changes in Skeletal Muscle CB1 Receptors by an in Vitro Model of Aging-related Muscle Atrophy
通过衰老相关性肌肉萎缩的体外模型分析骨骼肌 CB1 受体的年龄依赖性功能变化
- 批准号:
22KJ2960 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for JSPS Fellows
Joint U.S.-Japan Measures for Aging and Dementia Derived from the Prevention of Age-Related and Noise-induced Hearing Loss
美日针对预防与年龄相关和噪声引起的听力损失而导致的老龄化和痴呆症联合措施
- 批准号:
23KK0156 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Fund for the Promotion of Joint International Research (International Collaborative Research)
The Effects of Muscle Fatigability on Gait Instability in Aging and Age-Related Falls Risk
肌肉疲劳对衰老步态不稳定性和年龄相关跌倒风险的影响
- 批准号:
10677409 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Characterizing gut physiology by age, frailty, and sex: assessing the role of the aging gut in "inflamm-aging"
按年龄、虚弱和性别表征肠道生理学特征:评估衰老肠道在“炎症衰老”中的作用
- 批准号:
497927 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Role of AGE/RAGEsignaling as a driver of pathological aging in the brain
AGE/RAGE信号传导作为大脑病理性衰老驱动因素的作用
- 批准号:
10836835 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Deciphering the role of osteopontin in the aging eye and age-related macular degeneration
破译骨桥蛋白在眼睛老化和年龄相关性黄斑变性中的作用
- 批准号:
10679287 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Targeting Age-Activated Proinflammatory Chemokine Signaling by CCL2/11 to Enhance Skeletal Muscle Regeneration in Aging
通过 CCL2/11 靶向年龄激活的促炎趋化因子信号传导以增强衰老过程中的骨骼肌再生
- 批准号:
478877 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Operating Grants
Elucidation of the protein kinase NLK-mediated aging mechanisms and treatment of age-related diseases
阐明蛋白激酶NLK介导的衰老机制及年龄相关疾病的治疗
- 批准号:
23K06378 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Underlying mechanisms of age-related changes in ingestive behaviors: From the perspective of the aging brain and deterioration of the gustatory system.
与年龄相关的摄入行为变化的潜在机制:从大脑老化和味觉系统退化的角度来看。
- 批准号:
23K10845 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)