HIV infection-induced mitochondrial dysfunction and premature T cell aging
HIV感染引起的线粒体功能障碍和T细胞过早衰老
基本信息
- 批准号:10203459
- 负责人:
- 金额:$ 42.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-05 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:8-hydroxyguanosineAPEX1 geneAgingApoptosisBase Excision RepairsBiomedical ResearchButylated HydroxytolueneCD4 Positive T LymphocytesCRISPR/Cas technologyCardiovascular DiseasesCell AgingCell physiologyChronicComplementCysteineDNADNA DamageDNA MaintenanceDNA RepairDNA biosynthesisDNA copy numberDNA polymerase gammaDataDiseaseEctopic ExpressionElderlyEnvironmentEnzymesExhibitsExonucleaseExposure toFunctional disorderFundingGenetic RecombinationGoalsHIVHIV InfectionsHealthHydrogen PeroxideImmuneImmune responseImmunocompetenceImpairmentIndividualInfectionInflammatoryInstitutionKnock-outLeadMaintenanceMalignant NeoplasmsMediatingMitochondriaMitochondrial DNAMitochondrial ProteinsMorbidity - disease rateNerve DegenerationPathway interactionsPatientsPloidiesPolymeraseProductionProtein AnalysisProteinsProteomicsReactive Oxygen SpeciesRecoveryResearchRespirationRoleShort Interspersed Nucleotide ElementsSignal TransductionSmall Interfering RNAStudentsSuperoxidesT-Cell DepletionT-Cell ReceptorT-LymphocyteTelomere ShorteningTestingViralVirus Diseasesantiretroviral therapybaseclinically relevantendonuclease Gfunctional disabilitygraduate studentimprovedknock-downliquid chromatography mass spectrometrymitochondrial dysfunctionmortalitynovelnucleasenucleotide metabolismoverexpressionoxidative damageperoxiredoxin Iprematurepreventrepairedresponsesenescencesingle moleculestudent trainingsuperoxide dismutase 1undergraduate student
项目摘要
HIV infection-induced mitochondrial dysfunction and premature T cell aging
HIV infection appears to drive premature T cell aging, evidenced by mitochondrial dysfunction. How CD4 T cells
develop mitochondrial dysfunction during HIV infections is unclear. The objective of this proposal is to elucidate the
mechanisms of mitochondrial dysfunction during chronic HIV infection, so as to develop effective means to rescue
CD4 T cell depletion or functional impairment, the sine que non of HIV-infection. To elucidate the mechanisms
underlying mitochondrial dysfunction in CD4 T cell aging, we analyzed the mitochondrial function of CD4 T cells
derived from ART-controlled HIV patients. Our preliminary data show that HIV CD4 T cells have decreased
mitochondrial DNA (mtDNA) content, mitochondrial respiration, and ATP production. To identify candidate proteins
involved in dysregulating mtDNA copy numbers, we performed Liquid Chromatography Mass Spectrometry (LC-MS)
on purified mitochondria from CD4 T cells of HIV patients and health subjects (HS). We found largest reduction of
mitochondrial proteins (SOD1 and PRDX1) in destroying reactive oxygen species (ROS), and in repair of ROS-
mediated DNA damage repair (APEX1), and elevation of proteins in mtDNA degrading (EXOG and ENDOG) and
mtDNA replication (POLG and MGME1). Based on these and other preliminary data, we hypothesize that ROS-
mediated mtDNA damage (via lower SOD1 and/or PDRX1 and APEX1) may cause higher mtDNA degradation (by
EXOG and ENDOG), which may not be sufficiently complemented by mtDNA replication (through higher POLG and
MGME1), leading to lower mtDNA copy number and impaired mitochondrial functions that we have seen in HIV-
derived CD4 T cells. We propose two aims to define the mechanisms leading to mtDNA decrease and compromised
function. In Aim 1, We will determine if ectopic expression of SOD1 and/or PRDX1 can reduce ROS level and
oxidative mtDNA damage in CD4 T cells of HIV patients. In addition, ectopic expression of APEX1 will be performed
to determine the involvement of APEX1 in repairing damaged mtDNA via the base excision repair (BER) pathway.
siRNA knockdown of SOD1 and/or PRDX1, and APEX1 will also be performed in healthy CD4 T cells to confirm
their roles in mtDNA damage and copy number maintenance, mitochondrial respiration, and ATP production. In Aim
2, we will use transient siRNA knockdown or Crisper/Cas9 knockout to reduce the EXOG and/or ENDOG nucleases
in CD4 T cells from HIV patients, and to assess the levels of oxidative mtDNA damage and rescue of mtDNA copy
number. We will perform single molecule analysis of replicated DNA (SMARD) on mtDNA in cultured CD4 T cells
from HIV patients to comprehensively assess the status of mtDNA replication in response to T cell receptor (TCR)
stimulation. Overall, this application is novel and strong in both concept and approach to answer clinically relevant
questions: how chronic viral infection induces mitochondrial dysfunction, leading to premature T cells aging, and
whether interfering those over-activated enzymes responsible for mtDNA copy number reduction and mitochondrial
dysfunction can remodel T cell aging and function during HIV infection. Understanding such mechanisms is critical
for developing approaches to improve immune responses in the setting of many infectious or inflammatory diseases.
HIV infection-induced mitochondrial dysfunction and premature T cell aging
HIV infection appears to drive premature T cell aging, evidenced by mitochondrial dysfunction. How CD4 T cells
develop mitochondrial dysfunction during HIV infections is unclear. The objective of this proposal is to elucidate the
mechanisms of mitochondrial dysfunction during chronic HIV infection, so as to develop effective means to rescue
CD4 T cell depletion or functional impairment, the sine que non of HIV-infection. To elucidate the mechanisms
underlying mitochondrial dysfunction in CD4 T cell aging, we analyzed the mitochondrial function of CD4 T cells
derived from ART-controlled HIV patients. Our preliminary data show that HIV CD4 T cells have decreased
mitochondrial DNA (mtDNA) content, mitochondrial respiration, and ATP production. To identify candidate proteins
involved in dysregulating mtDNA copy numbers, we performed Liquid Chromatography Mass Spectrometry (LC-MS)
on purified mitochondria from CD4 T cells of HIV patients and health subjects (HS). We found largest reduction of
mitochondrial proteins (SOD1 and PRDX1) in destroying reactive oxygen species (ROS), and in repair of ROS-
mediated DNA damage repair (APEX1), and elevation of proteins in mtDNA degrading (EXOG and ENDOG) and
mtDNA replication (POLG and MGME1). Based on these and other preliminary data, we hypothesize that ROS-
mediated mtDNA damage (via lower SOD1 and/or PDRX1 and APEX1) may cause higher mtDNA degradation (by
EXOG and ENDOG), which may not be sufficiently complemented by mtDNA replication (through higher POLG and
MGME1), leading to lower mtDNA copy number and impaired mitochondrial functions that we have seen in HIV-
derived CD4 T cells. We propose two aims to define the mechanisms leading to mtDNA decrease and compromised
function. In Aim 1, We will determine if ectopic expression of SOD1 and/or PRDX1 can reduce ROS level and
oxidative mtDNA damage in CD4 T cells of HIV patients. In addition, ectopic expression of APEX1 will be performed
to determine the involvement of APEX1 in repairing damaged mtDNA via the base excision repair (BER) pathway.
siRNA knockdown of SOD1 and/or PRDX1, and APEX1 will also be performed in healthy CD4 T cells to confirm
their roles in mtDNA damage and copy number maintenance, mitochondrial respiration, and ATP production. In Aim
2, we will use transient siRNA knockdown or Crisper/Cas9 knockout to reduce the EXOG and/or ENDOG nucleases
in CD4 T cells from HIV patients, and to assess the levels of oxidative mtDNA damage and rescue of mtDNA copy
number. We will perform single molecule analysis of replicated DNA (SMARD) on mtDNA in cultured CD4 T cells
from HIV patients to comprehensively assess the status of mtDNA replication in response to T cell receptor (TCR)
stimulation. Overall, this application is novel and strong in both concept and approach to answer clinically relevant
questions: how chronic viral infection induces mitochondrial dysfunction, leading to premature T cells aging, and
whether interfering those over-activated enzymes responsible for mtDNA copy number reduction and mitochondrial
dysfunction can remodel T cell aging and function during HIV infection. Understanding such mechanisms is critical
for developing approaches to improve immune responses in the setting of many infectious or inflammatory diseases.
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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Zhi Q. Yao其他文献
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{{ truncateString('Zhi Q. Yao', 18)}}的其他基金
Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
针对 HBV/HIV 双重感染的纳米颗粒递送的双特异性基因编辑药物
- 批准号:
10403587 - 财政年份:2021
- 资助金额:
$ 42.76万 - 项目类别:
Mitochondrial Dysfunction in Aging CD4 T cells in HIV-immune Non-responders.
HIV 免疫无反应者中衰老 CD4 T 细胞的线粒体功能障碍。
- 批准号:
10845843 - 财政年份:2021
- 资助金额:
$ 42.76万 - 项目类别:
Dual specific gene editing drugs delivered by nanoparticles targeting HBV/HIV coinfection
针对 HBV/HIV 双重感染的纳米颗粒递送的双特异性基因编辑药物
- 批准号:
10161447 - 财政年份:2021
- 资助金额:
$ 42.76万 - 项目类别:
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- 批准号:
10265317 - 财政年份:2019
- 资助金额:
$ 42.76万 - 项目类别:
Telomere loss and T cell aging in HBV vaccine response in HCV-infected individual
HCV 感染者的 HBV 疫苗反应中的端粒丢失和 T 细胞老化
- 批准号:
10455526 - 财政年份:2019
- 资助金额:
$ 42.76万 - 项目类别:
Gender difference in miRNA-mediated T cell aging during viral infection
病毒感染期间 miRNA 介导的 T 细胞衰老的性别差异
- 批准号:
9896225 - 财政年份:2019
- 资助金额:
$ 42.76万 - 项目类别:
Premature T cell aging and vaccine failure in chronic viral infection
慢性病毒感染中 T 细胞过早衰老和疫苗失败
- 批准号:
9023117 - 财政年份:2016
- 资助金额:
$ 42.76万 - 项目类别:
ShEEP Proposal for a Multiuser Advanced Biosafe Flow Cytometer
ShEEP 针对多用户高级生物安全流式细胞仪的提案
- 批准号:
9211532 - 财政年份:2016
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Telomere attrition and T cell aging in vaccine failure during HIV infection
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- 批准号:
10581156 - 财政年份:2016
- 资助金额:
$ 42.76万 - 项目类别: