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
• 负责人: Schahram Akbarian
• 金额: $ 79.43万
• 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/10571875
• 关键词: 3-Dimensional; Affect; Autopsy; 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; Drug abuse; Elements; Epidemic; Exposure to; Freezing; Funding; Gene Expression; Genetic Transcription; Genome; Genomics; Goals; HIV; HIV Genome; HIV Infections; HIV-associated neurocognitive disorder; HIV/AIDS; Hi-C; High Prevalence; Human; Individual; Interview; Link; Maps; Microglia; Midbrain structure; Molecular Conformation; Monitor; National Institute of Drug Abuse; Neostriatum; Neuroanatomy; Neurobehavioral Manifestations; Neurobiology; Neurocognitive; Neurologic; Neurologic Symptoms; Neurological status; Neurons; Nuclear; Nuclear RNA; Opioid; Pathogenesis; Pathology; Pattern; Peripheral; Persons; Plasma; Population; Prefrontal Cortex; Process; RNA; RNA Probes; Recording of previous events; Resources; Site; Sorting; Statistical Data Interpretation; Structure; Substance Use Disorder; Substance abuse problem; Substantia nigra structure; Syndrome; Toxicology; Transcript; 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; genomic locus; high dimensionality; high risk; human tissue; innovation; insight; motor disorder; neural; neural circuit; neuroAIDS; neurogenomics; novel; opioid abuse; opioid exposure; programs; prospective; single nucleus RNA-sequencing; transcriptome; transcriptome sequencing; transcriptomic profiling; 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.

与艾滋病毒相关的神经认知障碍（手）持续存在于抗逆转录病毒的时代 治疗（购物车）。 HIV潜伏期和人类中枢神经系统中HIV转录本的细胞特异性表达 尽管与HIV相关的神经系统疾病和 在被购物车稳定抑制的人中，人们对中枢神经系统病毒逃生的认识越来越多。专业之一 有关CNS HIV需要研究的问题是HIV整合。换句话说，是否CNS HIV 整合具有生物学上的显着影响，导致发病机理？ CNS功能的问题 鸦片和其他物质使用的共同注册流行病使赤字更加复杂 艾滋病毒/艾滋病（PLWHA）的疾病（SUD），因为SUD也对CNS产生了深远的影响 功能，并有可能在艾滋病毒潜伏期上。中枢神经系统中没有比这更明显的 纹状体多巴胺能回路和额叶的神经解剖学重叠 投影，功能性和神经生物学疾病的偏好部位以及负担增加 艾滋病毒感染。因此，在神经学上直接利用这些区域中的脑组织 具有和没有SUD的艾滋病毒感染者的特征，此应用的目标是：（i） 重复大脑 将艾滋病毒宿主基因组整合和病毒潜伏期与核地形和开放染色质联系起来； （ii）到 探索多巴胺能回路中转录组和表观基因组中的HIV签名是否 包括额叶和纹状体靶标与前瞻性监测的神经系统有关 死亡和暴露于滥用药物之前的几年中的状况； （iii）探索潜力中的艾滋病毒表达 大脑的储层细胞，包括小胶质细胞。预计此处提出的创新实验 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 在受感染的大脑的神经基础状态与神经系统和认知症状之间 药物滥用。在认识到高风险方面的同时，这些分析仍将 可预测的高收益在理解复杂的艾滋病毒基础的复杂神经生物学方面的好处 PLWHA和SUD中的相关中枢神经系统疾病。