Single Cell Analysis of Epigenetic Mechanisms that Regulate HIV-1 CNS Latency and Neuropathogenesis
Single Cell Analysis of Epigenetic Mechanisms that Regulate HIV-1 CNS Latency and Neuropathogenesis
批准号:
10748578
负责人:
CRISTIAN COARFA
金额:
$88.56万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-06 至 2028-04-30
关键词:
Antiviral TherapyAutopsyBioinformaticsBloodBrainCD4 Positive T LymphocytesCell LineCell NucleusCellsCessation of lifeChromatinCognitionCognitiveCognitive deficitsCollectionDataDementiaDiagnosisEffectivenessEpigenetic ProcessGene ExpressionGenetic TranscriptionGoalsHIV-1HIV-associated neurocognitive disorderHigh PrevalenceHippocampusHumanIn VitroIndividualInfectionKnock-outLymphoid TissueMessenger RNAMicroRNAsMicrogliaMinorNeurocognitive DeficitNeuropathogenesisPersonsPrefrontal CortexPrior TherapyResearchRoleSample SizeSamplingSiteSpecimenTechnologyTherapeuticToxic effectUnited StatesUntranslated RNAValidationViralViral reservoirVirusVirus LatencyVirus ReplicationWorkantiretroviral therapycell typeexperimental studygene networkinduced pluripotent stem cellinsightlatent virus activationmotor disorderneuroAIDSneurocognitive disorderneurotropicnovelnovel therapeutic interventionoverexpressionreactivation from latencysingle cell analysissingle-cell RNA sequencingtranscriptome sequencing
中文摘要
目前的抗逆转录病毒疗法(ART)在大多数个体中成功地抑制了HIV-1复制。
英文摘要
Current antiretroviral therapies (ART) are successful in suppressing HIV-1 replication in most individuals.
However, cessation of ART results in emergence of HIV-1 from a latent viral reservoir, thereby requiring a
lifetime ART regime. The best-described HIV-1 reservoir is that of CD4+ T lymphocytes in circulating blood
and lymphoid tissues that contain a transcriptionally silent but replication-competent virus. The brain is also an
important viral reservoir site, but it is poorly characterized due to the challenges in obtaining specimens for
analyses. Despite its effectiveness, multiple toxicities are associated with ART, especially the high prevalence
of HIV-associated neurocognitive deficits. The research described in this application will use human autopsy
specimens to investigate two key issues regarding HIV-1 infection of the brain: 1) epigenetic mechanisms that
regulate active and latent HIV-1 infection in the brain; 2) mechanisms underlying neuropathogenesis and
neurocognitive deficits in HIV-1-infected individuals on suppressive ART. Brain specimens from prefrontal
cortex and hippocampus from HIV-1 infected individuals treated with ART death will be obtained from the
National NeuroAIDS Consortium. Matched HIV-1-negative control specimens will be obtained from the
UTHealth Brain Collection. Single cell RNA sequencing technology will be utilized to identify long noncoding
RNAs (lncRNAs), mRNAs, and microRNAs (miRNAs) that are dysregulated in HIV-1-infected individuals.
Validation experiments will be performed in HIV-1-infected microglia cells to identify dysregulated lncRNAs and
miRNAs that contribute to HIV-1 replication, latency, and neuropathogenesis. Completion of the proposed
work is likely to identify therapeutic approaches to treat HIV-1 infection of the brain.
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Systems Bioinformatics Core
-
批准号:10518175
-
项目类别:
-
资助金额:$7.95万
-
财政年份:2022
-
负责人:CRISTIAN COARFA
-
依托单位:
Systems Bioinformatics Core
-
批准号:10707163
-
项目类别:
-
资助金额:$6.31万
-
财政年份:2022
-
负责人:CRISTIAN COARFA
-
依托单位:
Epigenetic variation at metastable epialleles: Effects on human obesity
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批准号:9214997
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项目类别:
-
资助金额:$36.03万
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财政年份:2017
-
负责人:CRISTIAN COARFA
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依托单位:
海外基金