CELL - AND CIRCUIT - SPECIFIC EXPLORATION OF HIV NEUROGENOMICS IN CONTEXT OF OPIATE AND COCAINE ABUSE
细胞和电路 - 阿片类药物和可卡因滥用背景下 HIV 神经基因组学的具体探索
基本信息
- 批准号:10113577
- 负责人:
- 金额:$ 59.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAIDS/HIV problemAcuteAffectAntibodiesAreaAstrocytesAutopsyBiologicalBiological AssayBrainCD3 AntigensCD4 Positive T LymphocytesCD44 geneCell Culture TechniquesCell NucleusCell surfaceCellsCentral Nervous System DiseasesCessation of lifeChromatinChronicCocaineCocaine AbuseComplexCorpus striatum structureDNADSM-VDiagnosisDiagnosticDiseaseDocumentationDorsalDrug abuseEGF geneElementsEpidemicEpidermal Growth Factor ReceptorExposure toFreezingGenomeGenomicsGoalsHIVHIV GenomeHIV InfectionsHIV SeronegativityHIV-associated neurocognitive disorderHi-CHigh PrevalenceHumanITGAM geneIn Situ HybridizationIndividualInterviewLigandsLinkLocationLymphocyteMapsMicrogliaMidbrain structureMolecular ConformationMonitorMorphineNeostriatumNeurobehavioral ManifestationsNeurobiologyNeurocognitiveNeurologicNeurologic SymptomsNeurological statusNeuronsNeuropathogenesisNuclearNuclear PoreOligodendrogliaOpioidPTPRC genePathogenesisPeripheralPlasmaPopulationPrefrontal CortexRNARecording of previous eventsSiteSpleenStructureSubstance Use DisorderSubstance abuse problemSyndromeT-LymphocyteToxicologyTranscriptUrineViralViral Load resultVirus IntegrationVirus LatencyVirus Replicationantiretroviral therapybrain cellbrain tissuecell typecocaine exposurecohortcompliance behaviordeep sequencingdomain mappingdrug of abuseepigenomeepigenomicsexperimental studygenome-widehigh dimensionalityhigh riskhistone modificationhuman tissueinnovationinsightintegration sitelongitudinal analysislymph nodesnervous system disorderneural circuitneurogenomicsnovelopioid abuseopioid exposureprospectiverelating to nervous systemtranscriptome
项目摘要
HIV-associated neurocognitive disorders (HAND) persist in the era of combination antiretroviral therapy
(cART). Proof of HIV latency in human CNS is currently lacking, despite continued high prevalence of HIV-
associated neurologic disease and increasing recognition of CNS viral escape in people stably suppressed
with cART. One of the major issues regarding CNS HIV in need for study is HIV integration. With other words,
whether CNS HIV integration has biologically significant impact, contributing to pathogenesis? Issues of CNS
functional deficit are further complicated by the co-registered epidemic of opiate and other substance use
disorders (SUD) in people living with HIV/AIDS (PLWHA), as SUD also have profound impact on CNS function,
and potentially on HIV latency. Nowhere in the CNS is this more evident than in the neuroanatomic overlap of
HIV and SUD in striatonigral dopaminergic circuitry and frontostriatal projections, sites of predilection for
functional and neurobiologic disease as well as for increased burden of HIV infection. Accordingly, directly
utilizing brain tissues in these regions, from neurologically well-characterized HIV-infected individuals with and
without SUD, the goal of this application will be: (i) to replicate for brain some of the emerging genomic
mechanisms recently discovered in peripheral cells, linking HIV host genome integration and virus latency to
nuclear topography and open chromatin; (ii) to explore whether HIV signatures in transcriptomes and
epigenomes in dopaminergic circuitry is associated with prospectively monitored neurological status in the
years before death and exposure to drug of abuse; (iii) explore HIV expression and integration in potential
reservoir cells of the brain, including microglia and astrocytes derived from HIV+ brain at autopsy and (iv)
explore the impact of substance history on HIV integration and activity in primary microglial cultures derived
from HIV- brains at autopsy and (vi) expose primary microglia in culture to drugs of abuse and HIV. The
innovative experiments proposed here are expected to offer novel insights into epigenomic landscapes in
specific brain cells and explore potential links between neurogenomic status of the infected brain and
neurological and cognitive symptoms and substance abuse. While recognizing the high-risk aspects, these
analyses will nevertheless have predictable, high gain benefits in understanding the complex neurobiology
underlying HIV-associated CNS disease in PLWHA and SUD.
HIV相关神经认知障碍(HAND)在联合抗逆转录病毒治疗时代仍然存在
(cART)。目前缺乏HIV在人类CNS中潜伏的证据,尽管HIV的持续高流行率-
相关的神经系统疾病,并在稳定抑制的人群中越来越多地认识到CNS病毒逃逸
关于CART需要研究的有关中枢神经系统艾滋病毒的主要问题之一是艾滋病毒整合。换句话说,
CNS HIV整合是否具有生物学意义的影响,有助于发病机制?CNS问题
阿片剂和其他药物使用的共同登记流行使功能缺陷进一步复杂化
艾滋病毒/艾滋病(PLWHA)感染者的疾病(SUD),因为SUD对CNS功能也有深远的影响,
和潜在的HIV潜伏期。在中枢神经系统中,这一点在神经解剖学重叠中最为明显,
纹状体黑质多巴胺能回路和额纹状体投射中的HIV和SUD,
功能性和神经生物学疾病以及HIV感染负担的增加。因此,直接
利用这些区域的脑组织,来自神经学上特征良好的HIV感染者,
如果没有SUD,这项应用的目标将是:(i)为大脑复制一些新兴的基因组
最近在外周细胞中发现的机制,将HIV宿主基因组整合和病毒潜伏期联系起来,
核拓扑学和开放染色质;(ii)探索转录组中的HIV特征和
多巴胺能回路中的表观基因组与前瞻性监测的神经系统状态相关,
(iii)探讨艾滋病毒表达和整合的潜力
脑的储库细胞,包括尸检时来源于HIV+脑的小胶质细胞和星形胶质细胞,以及(iv)
探索药物史对HIV整合和活性的影响,
从HIV-脑尸检和(vi)暴露在文化的初级小胶质细胞滥用药物和艾滋病毒。的
这里提出的创新实验有望为表观基因组景观提供新的见解,
特定的脑细胞,并探索受感染大脑的神经基因组状态与
神经和认知症状以及药物滥用。虽然认识到高风险方面,
然而,分析将在理解复杂的神经生物学方面具有可预测的高增益益处。
PLWHA和SUD中潜在的HIV相关CNS疾病。
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)
Genomic Exploration of the Brain in People Infected with HIV-Recent Progress and the Road Ahead.
- DOI:10.1007/s11904-023-00675-9
- 发表时间:2023-12
- 期刊:
- 影响因子:4.6
- 作者:
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Schahram Akbarian其他文献
Schahram Akbarian的其他文献
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{{ truncateString('Schahram Akbarian', 18)}}的其他基金
Cell-lineage specific epigenomic determinants of HIV latency in humanized mouse brain and blood
人源化小鼠大脑和血液中HIV潜伏期的细胞谱系特异性表观基因组决定因素
- 批准号:
10747752 - 财政年份:2023
- 资助金额:
$ 59.37万 - 项目类别:
Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant
暴露于麻醉剂和兴奋剂的 HIV 脑细胞的单染色质纤维测序和纵向表观基因组分析
- 批准号:
10457112 - 财政年份:2022
- 资助金额:
$ 59.37万 - 项目类别:
Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant
暴露于麻醉剂和兴奋剂的 HIV 脑细胞的单染色质纤维测序和纵向表观基因组分析
- 批准号:
10595615 - 财政年份:2022
- 资助金额:
$ 59.37万 - 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
- 批准号:
10219584 - 财政年份:2021
- 资助金额:
$ 59.37万 - 项目类别:
Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain
在嵌合小鼠大脑中模拟 HIV 小胶质细胞相关的感染和炎症
- 批准号:
10458060 - 财政年份:2021
- 资助金额:
$ 59.37万 - 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
- 批准号:
10783382 - 财政年份:2021
- 资助金额:
$ 59.37万 - 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
- 批准号:
10571875 - 财政年份:2021
- 资助金额:
$ 59.37万 - 项目类别:
Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain
HIV大脑成瘾回路的单核转录组分析
- 批准号:
10381603 - 财政年份:2021
- 资助金额:
$ 59.37万 - 项目类别:
Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain
在嵌合小鼠大脑中模拟 HIV 小胶质细胞相关的感染和炎症
- 批准号:
10632139 - 财政年份:2021
- 资助金额:
$ 59.37万 - 项目类别:
Modeling HIV Microglia-Associated Infection and Inflammation in a Chimeric Mouse Brain
在嵌合小鼠大脑中模拟 HIV 小胶质细胞相关的感染和炎症
- 批准号:
10301839 - 财政年份:2021
- 资助金额:
$ 59.37万 - 项目类别: