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.

项目摘要患有艾滋病毒（PLWH）的人的认知功能受损的风险更高，例如与HIV相关的神经认知障碍或手。此外，更高使用法律和非法 PLWH中的阿片类药物可能会影响其免疫功能并加剧CNS损害。但是，关于大脑中含有细胞类型的艾滋病毒，艺术对特定的影响知之甚少 CNS细胞类型，以及通过使用阿片类药物的修饰。人的大脑是由由不同基因表达定义的细胞类型的多样性组成，形态，连通性和生理学。单细胞测序测定启用细胞类型 - 这些细胞类型在健康脑功能和疾病中的作用的具体分析。总体该提案的目的是揭示与持久性相关的大脑的单细胞决定因素使用SNRNA-SEQ和SNATAC-SEQ技术，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性药物一样伏隔核（NAC）和前额叶皮层（PFC），这两个区域也是受艾滋病毒影响。我们提出了一个前所未有的概念和实验系统，以识别与持续性HIV感染和阿片类药物使用障碍有关的大脑的单细胞决定因素作为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的目的：目标1：创建一个PFC和PFC的单核转录组图集 NAC。 SNRNA-SEQ将在从验尸后大脑中分离出来的这两个区域进行。目的 2：创建PFC和NAC的单个核表观基因组图。 SNATAC-SEQ将在这两个区域从验尸后的大脑中分离出来。这些创新的成功完成单细胞研究将生成两个与NIDA相关的大脑区域，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如何通过艾滋病毒和阿片类药物的使用来改变它们。