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

基本信息

批准号：
10220611
负责人：
TARIQ M RANA
金额：
$ 225.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2021-09-30 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220611
关键词：
AIDS therapy AIDS/HIV problem 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 Cerebrum Cessation of life Chromatin DNA Data Disease Elements Environment Enzymes Epigenetic Process Foxes Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genetic Variation Genome Glass HIV HIV Infections HIV-associated neurocognitive disorder Human Human Genome Immune Immune System Diseases Immunobiology Impaired cognition Impairment Individual Legal Measurement Methamphetamine Methods Modernization Modification Molecular Morphology Mus National Institute of Drug Abuse Neuraxis Neuroglia Nucleus Accumbens Opioid Organoids Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Physiology Prefrontal Cortex Proteins Rana Regulator Genes Regulatory Element Reporting Role Sampling Schizophrenia Site Small Nuclear RNA 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 disorder control 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-cell RNA sequencing transcription factor transcriptome transcriptomics validation studies virology

项目摘要

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.

项目概要艾滋病毒感染者 (PLWH) 认知功能受损的风险较高，例如 HIV 相关神经认知障碍或 HAND。此外，更多地使用合法和非法的艾滋病毒感染者中的阿片类药物可能会影响他们的免疫功能并加剧中枢神经系统损伤。然而，人们对大脑中 HIV 携带细胞类型、ART 对特定细胞的影响知之甚少。中枢神经系统细胞类型，以及阿片类药物使用对大脑功能的改变。人类的大脑是由由不同基因表达定义的巨大多样性细胞类型组成，形态、连通性和生理学。单细胞测序分析使细胞类型具体分析这些细胞类型在健康大脑功能和疾病中的作用。整体该提案的目的是揭示与持久性相关的大脑单细胞决定因素使用 snRNA-seq 和 snATAC-seq 技术的 HIV 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，会影响伏隔核 (NAc) 和前额皮质 (PFC)，这两个区域也受艾滋病毒影响。我们提出了前所未有的概念和实验系统来识别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以及阐明遗传变异如何影响基因表达的潜在机会。我们的项目有两个具体目标：目标 1：创建 PFC 和 PFC 的单核转录组图谱 NAc。 snRNA-seq 将对从死后大脑中分离出的这两个区域进行。目的 2：创建 PFC 和 NAc 的单核表观基因组图谱。 snATAC-seq 将在这两个区域与死后大脑分离。这些创新成果的顺利完成单细胞研究将为两个 NIDA 相关的大脑区域（PFC 和 NAc，并将阐明中枢神经系统转录组和表观遗传景观的新见解以及它们如何因艾滋病毒和阿片类药物的使用而改变。