Can Senolytics Improve the Aged Response to Viral Infection
Can Senolytics Improve the Aged Response to Viral Infection
批准号:
10475231
负责人:
Laura Haynes
金额:
$20.5万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-01 至 2024-05-31
关键词:
Adaptive Immune SystemAddressAgeAgingAntibodiesAntibody AffinityAntibody FormationAtrophicAutomobile DrivingBacterial InfectionsBody Weight decreasedCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCause of DeathCell AgingCellsChronologyClinical TrialsCommunicable DiseasesDiseaseDown-RegulationElderlyFOXP3 geneFast-Twitch Muscle FibersFunctional disorderGaitGene ExpressionGenerationsGenesGrowthHistologyImmune responseImmune systemImmunization ProgramsImmunologicsImpairmentInflammationInflammatoryInfluenzaIrrigationLungMolecularMusMuscleMuscle FibersMuscular AtrophyPathologyPharmaceutical PreparationsPhenotypePhysical FunctionPhysiologicalPlayProcessProductionPulmonary InflammationRecoveryRegulatory T-LymphocyteResearchRoleSerumSkeletal MuscleStressTestingTimeTissuesUp-RegulationViralVirusVirus Diseasesadaptive immune responseage relatedagedaging populationbasechemokinecytokinedisabilityeffector T cellexperienceflufunctional declinefunctional disabilityfunctional outcomesgene functionhuman modelhuman subjectimmune functionimmune system functionimprovedinfluenza infectionloss of functionmortalitymouse modelmuscle agingnew therapeutic targetpreclinical studypreventresilienceresponsesenescenceside effectwalking speed
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Influenza (flu) is foremost among all infectious diseases causing death and disability in older adults,
despite widespread vaccination programs. Age-related changes in the immune system contribute to declines in
the ability to mount a highly protective immune response following flu infection in both humans and mouse
models. With advancing age, we observe slower viral clearance and lingering lung inflammation, which could
set the stage for secondary bacterial infection. Importantly, aging impacts almost every aspect of the adaptive
immune response including generation of virus-specific CD4 and CD8 T cell effectors and high affinity antibody
production. While flu infection is entirely localized to the lungs, functional decrements in skeletal muscle are
also observed with upregulation of inflammatory and atrophy genes and downregulation of positive muscle
regulators, ultimately resulting in loss of physical function. Importantly, the impact of flu infection on these
molecular changes and overall functional declines is more pronounced and prolonged with aging, suggesting
decreased physiologic resilience. Even though much research has been done, the ultimate cause of these
age-related decrements has not been elucidated.
One of the most prominent features of aging is the accumulation of senescent cells and in this project
we will explore their role in the age-related changes in response to flu infection. Cellular senescence is
characterized by irreversible growth arrest that occurs when cells experience a range of stresses. The number
of senescent cells increases with chronological aging, resulting in many age-related pathologies and disease.
Factors secreted by senescent cells can also have a direct impact on surrounding cells driving dysfunction and
influencing cell subset differentiation. Interestingly, many of these factors are cytokines that are of vital
importance for an effective anti-viral immune response. Senescent cells play a causal role in the progression of
many age-related disorders, indicating that clearance of senescent cells might slow down the entire aging
process. Importantly, we and others have started to develop drugs, which can specifically kill senescent cells
(termed senolytics). Intermittent administration of senolytics can alleviate a range of age-related diseases.
However, the impact of senolytics on immune system function in aged population has not yet been examined.
The overall hypothesis that we will be addressing in this proposal is that senescent cells play a
causal role in the age-related impaired response to flu infection. We will test this hypothesis by eliminating
senescent cells in aged mice using senolytic drugs. This approach will allow us to simultaneously examine the
role of cellular senescence in the compromised immune response and the associated changes in skeletal
muscle and declines in physical function during flu infection in an aged mouse model.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1038/s41421-023-00567-7
发表时间:
2023-08-08
期刊:
CELL DISCOVERY
影响因子:
33.5
作者:
[He, Jing, Lin, Mingen, Zhang, Xinchao, Zhang, Ruonan, Tian, Tongguan, Zhou, Yuefan, Dong, Wenjing, Yang, Yajing, Sun, Xue, Dai, Yue, Xu, Yue, Zhang, Zhenru, Xu, Ming, Lei, Qun-Ying, Xu, Yanping, Lv, Lei]
通讯作者:
Lv, Lei
Human Rotator Cuff Tears Reveal an Age-Dependent Increase in Markers of Cellular Senescence and Selective Removal of Senescent Cells With Dasatinib + Quercetin Increases Genetic Expression of COL1A1 In Vitro.
人类肩袖撕裂揭示了细胞衰老标志物的年龄依赖性增加,并且用达沙替尼槲皮素选择性去除衰老细胞可增加体外 COL1A1 的基因表达。
DOI:
10.1016/j.arthro.2023.05.036
发表时间:
2024
期刊:
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association
影响因子:
--
作者:
[Hawthorne,BenjaminC, Wellington,IanJ, Sabitsky,JoshuaT, Murphy,KyleV, Karsmarski,OwenP, Thomas,RohinO, LeVasseur,MatthewR, Mancini,MichaelR, Trudeau,MaxwellT, Gulati,Sagar, McCarthy,MaryBethR, Cote,MarkP, Xu,Ming, Mazzocca,August]
通讯作者:
Mazzocca,August
The impact of senescence on immune memory
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批准号:10646811
-
项目类别:
-
资助金额:$45.32万
-
财政年份:2023
-
负责人:Laura Haynes
-
依托单位:
Can Senolytics Improve the Aged Response to Viral Infection
-
批准号:10303445
-
项目类别:
-
资助金额:$24.6万
-
财政年份:2021
-
负责人:Laura Haynes
-
依托单位:
Biomarkers Core RC3
-
批准号:10294032
-
项目类别:
-
资助金额:$22.42万
-
财政年份:2021
-
负责人:Laura Haynes
-
依托单位:
Biomarkers Core RC3
-
批准号:10668326
-
项目类别:
-
资助金额:$22.12万
-
财政年份:2021
-
负责人:Laura Haynes
-
依托单位:
Impact of Aging and Influenza Infection on Muscle Health
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批准号:9764231
-
项目类别:
-
资助金额:$20.84万
-
财政年份:2018
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负责人:Laura Haynes
-
依托单位:
ENHANCING AGED CD4 COGNATE FUNCTION WITH CYTOKINES
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批准号:7459706
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项目类别:
-
资助金额:$45.19万
-
财政年份:2007
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负责人:Laura Haynes
-
依托单位:
ANIMAL BREEDING
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批准号:7459709
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项目类别:
-
资助金额:$14.47万
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财政年份:2007
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负责人:Laura Haynes
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依托单位:
Aging and Immunity Workshop
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批准号:6836656
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项目类别:
-
资助金额:$1.02万
-
财政年份:2004
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负责人:Laura Haynes
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依托单位:
Aging and Immunity to Infection
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批准号:8727879
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项目类别:
-
资助金额:$6.25万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Aging and Immunity to Infection
-
批准号:8733490
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项目类别:
-
资助金额:$194.89万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Aging and Immunity to Infection
-
批准号:9226656
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项目类别:
-
资助金额:$6.08万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Influence of aging on T follicular helper (Tfh) cells
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批准号:9104074
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项目类别:
-
资助金额:$36.44万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Administration
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批准号:8261744
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项目类别:
-
资助金额:$8.81万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Impact of Aging on CD4 Immunity to Flu
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批准号:8733491
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项目类别:
-
资助金额:$43.15万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Impact of Aging on CD4 Immunity to Flu
-
批准号:8485478
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项目类别:
-
资助金额:$40.78万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Aging and Immunity to Infections
-
批准号:7560468
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项目类别:
-
资助金额:$240.24万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Impact of Aging on CD4 Immunity to Flu
-
批准号:8892013
-
项目类别:
-
资助金额:$42.13万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Aging and Immunity to Infection
-
批准号:8213918
-
项目类别:
-
资助金额:$189.06万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Administration
-
批准号:8485483
-
项目类别:
-
资助金额:$6.61万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
Administration
-
批准号:8733496
-
项目类别:
-
资助金额:$8.1万
-
财政年份:2003
-
负责人:Laura Haynes
-
依托单位:
海外基金