Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations
Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations
批准号:
10573380
负责人:
Peter Jesse Gaskill
金额:
$69.51万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-15 至 2027-06-30
关键词:
AddressAffectAmericanAnatomyAtlasesAwarenessBenzodiazepinesBrainCellsChromatinClinicalComplexDNADataData CorrelationsDevelopmentDiseaseDoseEpigenetic ProcessFailureGene Expression ProfileGeneticGenetic TranscriptionHIVHIV InfectionsHIV-1HumanImageIndividualInfectionInfection preventionMediatingMicrogliaMyelogenousMyeloid CellsNeuraxisNeurocognitiveNeuropathogenesisOutcomePenetrancePersonsPharmaceutical PreparationsPopulationProcessProductionProtocols documentationProvirusesPublishingRUNX1 geneRecrudescencesRegulationRiskRoleSmall Interfering RNASourceSubstance Use DisorderSymptomsTestingTherapeuticTranscription ProcessTranscriptional RegulationViralViral reservoirVirionVirusVirus ReplicationVulnerable PopulationsXanaxabuse liabilityantiretroviral therapybenzodiazepine misusecell typechromatin immunoprecipitationchronic infectiondrug misuseepigenetic regulationgag Gene Productsinduced pluripotent stem cellknock-downmacrophagememory CD4 T lymphocytemonocytemutantneuroAIDSneuroinflammationnovel therapeuticsprogramsreactivation from latencyrecruitreduce symptomsviral DNAviral RNA
中文摘要
治疗艾滋病毒的主要障碍之一是存在于不同的隔室和病毒库
英文摘要
One of the principal obstacles to curing HIV is the existence of viral reservoirs in distinct compartments and
cell types that are unaffected by antiretroviral therapy (ART). In the central nervous system (CNS), these
reservoirs are comprised of myeloid cells, such as perivascular macrophages and microglia. Critically, these
reservoirs are generally established prior to the initiation of ART and the presence of ART in the CNS does not
affect the established reservoir in long-lived myeloid populations. Thus, even in individuals on suppressive ART,
persistently infected CNS macrophages and microglia can drive ongoing neuroinflammation and provide a
source of HIV for viral recrudescence during medication hiatus or failure. Our ability to eliminate these reservoirs
is severely limited by the lack of understanding of the transcriptional and epigenetic regulation of HIV in myeloid
cells. To effectively target and eliminate CNS reservoirs in people living with HIV (PLWH), it is critical to define
the transcriptional mechanisms mediating persistent infection in distinct CNS myeloid populations.
The impact of HIV infection in the CNS is heightened in PLWH who have substance use disorders, including
those who take and/or misuse therapeutic drugs such as benzodiazepines (BDZ). Benzodiazepines are used by
more than 30 million Americans, have high abuse liability and misuse of these drugs accounts for 15 – 20% of
their use. Benzodiazepines are prescribed to a growing number of PLWH and are associated with an increased
risk of neurocognitive symptoms in this population. Little is known about the mechanisms by which BDZ impact
HIV neuropathogenesis. Our published and preliminary data indicate that BDZ can alter the transcriptional
regulation of HIV infection. To better understand and treat the development of neuroHIV in PLWH who use and/or
misuse BDZ, it is vital to determine who benzodiazepines affect the transcriptional programs in myeloid cells.
We hypothesize that both macrophages and microglia enter a semi-quiescent transcriptional state
during ART exposure and that benzodiazepines disrupt this state and increase transcriptional activity
and viral replication. Our data show that the BDZ Xanax, as well as some latency reactivation agents, mediate
a dose-dependent increase in p24 production in infected, ART-treated cells. Our preliminary studies suggest
these effects may result from BDZ interactions with the epigenetic regulator RUNX1. We posit that these changes
in HIV replication in myeloid cells reflect the epigenetic state of the provirus. Thus, the growing population of
PLWH who use BDZ is at greater risk of more severe neuropathogenesis. It also suggests that BDZ may provide
the basis for novel therapeutics to manipulate HIV transcription in myeloid cells. Therefore, we will evaluate the
transcriptional and epigenetic mechanisms sustaining the semi-quiescent state of HIV transcription in ART-
treated human macrophages (Aim 1), define the differences in transcriptional and epigenetic processes in
different types of myeloid cells using human syngeneic iPSC-derived macrophages and microglia (Aim 2), and
examine the effect of benzodiazepines on transcription HIV-infected, ART-treated myeloid cells (Aim 3).
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会议论文
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批准号:10685160
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项目类别:
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资助金额:$57.03万
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负责人:Peter Jesse Gaskill
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依托单位:
Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations
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批准号:10700122
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DAT-Psychostimulant mediated dopamine release increases macrophage IL-1beta production through NF-kB activation and inflammasome priming
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批准号:9978381
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Mechanisms of dopamine mediated increase in HIV infection of macrophages
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批准号:9333313
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资助金额:$40.02万
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财政年份:2015
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Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
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批准号:8040993
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资助金额:$14.61万
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财政年份:2010
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负责人:Peter Jesse Gaskill
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Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
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批准号:9185430
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资助金额:$0.59万
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财政年份:2010
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依托单位:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
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批准号:8637953
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项目类别:
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资助金额:$14.02万
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财政年份:2010
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负责人:Peter Jesse Gaskill
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依托单位:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
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批准号:8242055
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项目类别:
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资助金额:$14.61万
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财政年份:2010
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负责人:Peter Jesse Gaskill
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依托单位:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
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批准号:8446427
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项目类别:
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资助金额:$14.61万
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财政年份:2010
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负责人:Peter Jesse Gaskill
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依托单位:
Dopamine Exacerbates NeuroAIDS by Activation of Macrophage Dopaminergic System
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批准号:7929994
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项目类别:
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资助金额:$14.34万
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财政年份:2010
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负责人:Peter Jesse Gaskill
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依托单位:
Macrophages and dopamine: a role in NeuroAIDS
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批准号:7495386
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项目类别:
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资助金额:$4.96万
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财政年份:2008
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负责人:Peter Jesse Gaskill
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依托单位:
Macrophages and dopamine: a role in NeuroAIDS
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批准号:7636880
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项目类别:
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资助金额:$1.48万
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财政年份:2008
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负责人:Peter Jesse Gaskill
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依托单位:
海外基金