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

基本信息

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
项目类别：
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

项目摘要

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.

HIV相关神经认知障碍（HAND）在联合抗逆转录病毒药物时代持续存在疗法（cART）。 HIV潜伏期和人类中枢神经系统中HIV转录物的细胞特异性表达仍然存在尽管与艾滋病毒相关的神经系统疾病的患病率持续居高不下，越来越多的人认识到在 cART 稳定抑制的人群中中枢神经系统病毒逃逸。主要之一关于中枢神经系统HIV需要研究的问题是HIV整合。换句话说，CNS HIV 是否整合具有生物学上的重大影响，有助于发病机制？中枢神经系统功能问题阿片剂和其他物质使用的共同流行使赤字进一步复杂化 HIV 感染者/艾滋病患者 (PLWHA) 的疾病 (SUD)，因为 SUD 也对中枢神经系统产生深远影响功能，并可能影响 HIV 潜伏期。在中枢神经系统中，这一点比在中枢神经系统中表现得更明显。 HIV 和 SUD 在纹状体黑质多巴胺能回路和额纹状体中的神经解剖学重叠功能性和神经生物学疾病以及负担增加的预测、好发部位艾滋病毒感染。因此，直接利用这些区域的脑组织，从神经学角度来看，描述了有或没有 SUD 的 HIV 感染者，该应用的目标是：(i) 为大脑复制最近在外周细胞中发现的一些新兴基因组机制，将 HIV 宿主基因组整合和病毒潜伏期与核形貌和开放染色质联系起来； (二) 至探索多巴胺能回路中转录组和表观基因组中的 HIV 特征是否存在包括额叶和纹状体目标与前瞻性监测的神经系统相关死亡前几年的状况以及接触滥用药物的情况； (iii) 探索HIV表达的潜力大脑的储存细胞，包括小胶质细胞。这里提出的创新实验是预期的为特定脑细胞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药物滥用。虽然认识到高风险方面，但这些分析仍将有在理解 HIV 背后的复杂神经生物学方面可预测的、高收益的益处 PLWHA 和 SUD 中相关的 CNS 疾病。