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
• 负责人: Schahram Akbarian
• 金额: $ 79.6万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219584
• 关键词: 3-Dimensional; AIDS/HIV problem; Affect; Autopsy; Biological; Brain; CD4 Positive T Lymphocytes; Cell Count; Cell Nucleus; Cells; Central Nervous System Diseases; Cessation of life; Chromatin; Chromosomes, Human, 6-12 and X; Chronic; Clinical; Clinical Data; Cocaine; Cocaine Abuse; Complex; Corpus striatum structure; DNA; DSM-V; Data; Diagnosis; Diagnostic; Disease; Documentation; Dorsal; Drug abuse; Elements; Epidemic; Exposure to; Freezing; Funding; Gene Expression; Genetic Transcription; Genome; Genomics; Goals; HIV; HIV Genome; HIV Infections; HIV-associated neurocognitive disorder; Hi-C; High Prevalence; Human; Individual; Interview; Link; Location; Maps; Microglia; Midbrain structure; Molecular Conformation; Monitor; National Institute of Drug Abuse; Neostriatum; Neurobehavioral Manifestations; Neurobiology; Neurocognitive; Neurologic; Neurologic Symptoms; Neurological status; Neurons; Nuclear; Nuclear RNA; Opioid; Pathogenesis; Pathology; Pattern; Peripheral; Plasma; Population; Prefrontal Cortex; Process; RNA; RNA Probes; Recording of previous events; Resources; Site; Small Nuclear RNA; Sorting - Cell Movement; Statistical Data Interpretation; Structure; Substance Use Disorder; Substance abuse problem; Substantia nigra structure; Syndrome; Toxicology; Transcript; Transcription Alteration; Urine; Viral; Virus Latency; addiction; antiretroviral therapy; brain cell; brain tissue; case control; cell type; cocaine exposure; cohort; comorbidity; compliance behavior; drug of abuse; epigenome; experimental study; genome-wide; genomic data; high dimensionality; high risk; human tissue; innovation; insight; motor disorder; nervous system disorder; neural circuit; neurogenomics; novel; opioid abuse; programs; prospective; relating to nervous system; transcriptome; transcriptome sequencing; transcriptomics

HIV-associated neurocognitive disorders (HAND) persist in the era of combination antiretroviral therapy (cART). HIV latency, and cell-specific expression of HIV transcript in human CNS remains incompletely understood, 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 including frontal and striatal targets is associated with prospectively monitored neurological status in the years before death and exposure to drug of abuse; (iii) explore HIV expression in potential reservoir cells of the brain, including microglia. The innovative experiments proposed here are expected to offer novel insights into transcriptomic 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.

艾滋病毒相关神经认知障碍（HAND）在联合抗逆转录病毒时代持续存在 治疗（cART）HIV潜伏期和HIV转录物在人CNS中的细胞特异性表达仍然存在 尽管艾滋病毒相关神经系统疾病的患病率仍然很高， 增加对cART稳定抑制人群中CNS病毒逃逸的认识。的一个主要 关于中枢神经系统艾滋病毒的问题需要研究的是艾滋病毒的整合。换句话说，中枢神经系统艾滋病毒 整合有生物学意义的影响，有助于发病机制？CNS功能问题 鸦片剂和其他药物使用的共同登记流行使赤字进一步复杂化 艾滋病毒/艾滋病（PLWHA）感染者的疾病（SUD），因为SUD对CNS也有深远的影响。 功能，并可能对艾滋病毒潜伏期。在中枢神经系统中，这一点比在 HIV和SUD在纹状体黑质多巴胺能回路和额纹状体的神经解剖学重叠 预测，功能和神经生物学疾病以及负担增加的好发部位 艾滋病毒感染。因此，直接利用这些区域的脑组织，从神经学上讲， 特征的HIV感染的个体，有和没有SUD，本申请的目标将是：（i） 为大脑复制最近在外周细胞中发现的一些新兴的基因组机制， 将HIV宿主基因组整合和病毒潜伏期与核拓扑学和开放染色质联系起来;（ii） 探讨多巴胺能神经回路中转录组和表观基因组中的HIV特征 包括额叶和纹状体靶点与前瞻性监测的神经系统相关 在死亡和暴露于药物滥用前几年的状况;（iii）探索潜在的艾滋病毒表达 大脑的储库细胞，包括小胶质细胞。这里提出的创新实验是令人期待的 为特定脑细胞中的转录组景观提供新的见解，并探索潜在的联系 受感染大脑的神经基因组状态与神经和认知症状之间的关系， 滥用药物虽然认识到高风险的方面，但这些分析仍将 可预测的，高增益的好处，在了解复杂的神经生物学基础艾滋病毒- PLWHA和SUD中的相关CNS疾病。