Revealing the single cell determinants of brain relevant to persistent HIV infection and opioid use disorder

揭示与持续艾滋病毒感染和阿片类药物使用障碍相关的大脑单细胞决定因素

• 批准号: 10686140
• 负责人: TARIQ M RANA
• 金额: $ 223.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686140
• 关键词: ATAC-seq; Acquired Immunodeficiency Syndrome; Affect; Agreement; Anatomy; Animal Model; Atlases; Autopsy; BRAIN initiative; Binding; Bioinformatics; Biological Assay; Bipolar Disorder; Brain; Brain region; Cell Nucleus; Cells; Censuses; Central Nervous System; Cerebrum; Cessation of life; Chromatin; DNA; Data; Disease; Elements; Environment; Enzymes; Epigenetic Process; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Genetic Variation; Genome; Glass; HIV; HIV Infections; HIV-associated neurocognitive disorder; HIV/AIDS; Hand; Human; Human Genome; Immune; Immune System Diseases; Immunobiology; Impaired cognition; Impairment; Individual; Learning; Legal; Measurement; Methamphetamine; Methods; Modernization; Modification; Molecular; Morphology; Mus; National Institute of Drug Abuse; Neuroglia; Nucleus Accumbens; Opioid; Organoids; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Physiology; Prefrontal Cortex; Proteins; Rana; Regulator Genes; Regulatory Element; Reporting; Role; Sampling; Schizophrenia; Site; Specific qualifier value; System; Technology; Tissues; Transposase; United States National Institutes of Health; Untranslated RNA; Validation; Variant; Work; antiretroviral therapy; brain cell; brain dysfunction; cell type; cognitive function; data resource; epigenome; epigenomics; exhaustion; frontal lobe; high risk; immune function; induced pluripotent stem cell; innovation; insight; member; neuroinflammation; novel; opioid use; opioid use disorder; prevent; programs; single cell sequencing; single nucleus RNA-sequencing; single-cell RNA sequencing; transcription factor; transcriptome; transcriptomics; validation studies

PROJECT SUMMARY People living with HIV (PLWH) are at the higher risk for impaired cognitive functions such as HIV-Associated Neurocognitive Disorder or HAND. Further, higher use of legal and illegal opioids among PLWH could affect their immune functions and exacerbate CNS impairment. However, little is known about the HIV harboring cell types in brain, effect of ART on specific CNS cell types, and the modification of brain functions by opioid use. The human brain is composed of an enormous diversity of cell types defined by distinct gene expression, morphology, connectivity, and physiology. Single cell sequencing assays enable cell type- specific analysis of the role of these cell types in healthy brain function and disease. The overall objective of this proposal is to reveal the single cell determinants of brain relevant to persistent HIV infection and opioid use disorder using snRNA-seq and snATAC-seq technologies, bioinformatics approaches, and validation studies. Opioids, as with other addictive drugs, affect nucleus accumbens (NAc) and prefrontal cortex (PFC) and both of these regions are also affected by HIV. We put forward an unprecedented concept and experimental system to identify single cell determinants of brain relevant to persistent HIV infection and opioid use disorder as well as potential opportunities to illuminate how genetic variation affects gene expression. Our project has two specific aims: Aim 1: Create a single nucleus transcriptomic atlas of PFC and NAc. snRNA-seq will be performed on these two regions isolated from post mortem brains. Aim 2: Create a single nucleus epigenomic atlas of PFC and NAc. snATAC-seq will be performed on these two regions isolated from post mortem brains. Successful completion of these innovative single-cell studies will generate cellular part list for two NIDA-relevant brain regions, PFC and NAc, and will illuminate novel insights into transcriptomic and epigenetic landscapes of CNS and how they are altered by HIV and opioid use.

项目摘要 艾滋病毒感染者（PLWH）的认知功能受损的风险更高， HIV相关的神经认知障碍或手。此外，更多地使用法律的和非法的 阿片类药物可影响PLWH患者的免疫功能，加重中枢神经系统损害。 然而，关于脑中携带HIV的细胞类型、ART对特异性 中枢神经系统细胞类型，以及阿片类药物使用对脑功能的改变。人脑是 由不同的基因表达所定义的细胞类型的巨大多样性组成， 形态学、连通性和生理学。单细胞测序分析可实现细胞类型- 具体分析这些细胞类型在健康脑功能和疾病中的作用。整体 这项提议的目的是揭示与持久性脑损伤相关的脑单细胞决定因素， 使用snRNA-seq和snATAC-seq技术的艾滋病毒感染和阿片类药物使用障碍， 生物信息学方法和验证研究。阿片类药物与其他成瘾药物一样， 前额叶皮层（PFC）和前额叶核（NAc），这两个区域也 受艾滋病毒感染。我们提出了一个前所未有的概念和实验系统来识别 与持续性艾滋病毒感染和阿片类药物使用障碍相关的脑单细胞决定因素 以及阐明遗传变异如何影响基因表达的潜在机会。我们 该项目有两个具体目标：目标1：创建PFC的单核转录组图谱， NAc。snRNA-seq将在从死后脑分离的这两个区域上进行。目的 2：创建PFC和NAc的单核表观基因组图谱。snATAC-seq将在 这两个区域是从死后的大脑中分离出来的成功完成这些创新 单细胞研究将产生两个NIDA相关脑区的细胞部分列表，PFC和 NAc，并将阐明对CNS转录组和表观遗传景观的新见解 以及它们是如何被艾滋病毒和阿片类药物改变的。