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：
10381603
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
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/10381603
关键词：
3-Dimensional AIDS/HIV problem 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 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 Persons 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 neural circuit neuroAIDS 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.

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。