Elucidating single cell changes in neurogenic brain regions during HIV and cannabinoid exposure

阐明艾滋病毒和大麻素暴露期间神经源性大脑区域的单细胞变化

基本信息

批准号：
10686685
负责人：
Michael Jay Corley
金额：
$ 253.11万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686685
关键词：
Address Age Anti-Inflammatory Agents Area Autopsy Binding Sites Brain Brain region Cannabidiol Cannabinoids Cannabis Cell Nucleus Cells Cellular Assay Central Nervous System Cerebrospinal Fluid Cerebrum Chromatin Complement Controlled Study DNA-Binding Proteins Data Data Set Disease Dose Drug abuse Epigenetic Process Exposure to Frequencies Funding Gene Expression Genes Genetic Transcription Genomics Goals HIV HIV Infections HIV-associated cognitive impairment Hippocampus Human Immunohistochemistry Impairment Individual Inflammation Interferons Knowledge Measures Mediator Medicine Methods Microglia Modeling Myelogenous Neurobiology Neuronal Injury Neurons Neuropathogenesis Oral Oral Administration Organoids Outcome Pathogenicity Pathway interactions Pattern Persons Pharmacology Proliferating Protocols documentation Proviruses RNA Recreation Regimen Regulator Genes Reproducibility Research Research Personnel Risk Role SIV Specimen Structure Tetrahydrocannabinol Therapeutic Tissue Sample Tissues Toxic effect Transcript Transposase United States National Institutes of Health Validation Viral Viral Load result Virus XCL1 gene adult neurogenesis antiretroviral therapy bioinformatics pipeline brain cell brain tissue cell type comorbidity dentate gyrus epigenomics experience genome-wide histone modification improved lateral ventricle marijuana use marijuana use disorder multiple omics nerve stem cell neuroAIDS neurogenesis neuroinflammation neuron loss neuroprotection nonhuman primate pharmacologic programs response single cell technology subventricular zone transcriptomics

项目摘要

PROJECT SUMMARY (ABSTRACT) The use of cannabis for recreation and medicinal purposes is disproportionately high among people living with HIV (PLWH) and nearly half of cannabis using PLWH are estimated to be at risk for cannabis use disorder. Yet, whether cannabis is therapeutic or detrimental on the central nervous system (CNS) of PLWH remains controversial, highlighting the need for well-controlled studies generating reproducible data from specific cannabinoids, brain regions, and CNS cell types. Our research has shown that cell-type specific epigenetic patterns relate to HIV-associated cognitive impairment in PLWH, more frequent or recent cannabis use may reduce myeloid inflammation and impact brain structure in PLWH, and our recent single cell studies of the CNS in PLWH revealed distinct CSF microglia-like cells expressing CD204 in PLWH and ongoing HIV viral transcription in cerebrospinal fluid cells despite ART. Prior research has shown neurogenic brain regions including the subventricular zone of the lateral ventricles and hippocampus are of high relevance to persistent HIV infection and cannabinoid exposures. However, critical gaps in understanding neurogenic brain regions at single cell level in the setting of HIV and cannabinoid exposures remain. We are leveraging brain tissues from an established oral dosing model of cannabidiol and THC in a nonhuman primate (NHP) model of HIV, application of new single cell technologies permitting the simultaneous profiling of gene expression and open chromatin from the same cell (10X Genomics Multiome: RNA+ATAC) in brain tissues, a new single cell assay capable of measuring multiple histone modifications, and pharmacological profiling of current ART regimens and cannabinoid levels in brain tissues. Our central hypothesis is a therapeutic role of cannabinoids in ameliorating HIV neuropathogenesis in the CNS by enhancing the proliferation and survival of neural progenitor cells and immature neurons and reducing glial inflammation. To identify cell types, epigenetic cell states, and gene pathways relevant to neuropathogenesis, viral persistence, and cannabinoid exposures, we are harnessing 180 brain tissue samples from an established oral administration of either cannabidiol (CBD) or Δ9- tetrahydrocannabinol (THC) in NHP and single cell assays (10X Genomics single nucleus multiome and a new single cell assay developed at the NYGC capable of measuring the genome-wide presence of multiple histone modifications and protein-DNA binding sites). Moreover, accompanying single cell data will be generated from conserved neurogenic brain regions of human postmortem brain tissues from 40 donors based on HIV status (+/-) and cannabis exposure (+/-). We will also explore the frequency of single cells in neurogenic regions of the brain that are infected and impacted by cannabinoids by harnessing a bioinformatics pipeline that detects both viral transcripts and transposase accessible provirus. This project will generate comprehensive single cell datasets in NHP and humans to improve our understanding of the cross talk between HIV and cannabinoids in neurogenic regions of the brain and has high programmatic priority to goals of the SCORCH program expansion.

项目摘要（摘要）在居住的人中，将大麻用于娱乐和医疗目的的人不成比例据估计，使用PLWH的HIV（PLWH）和几乎一半的大麻有大麻使用障碍的风险。然而， PLWH的中枢神经系统（CNS）是否具有治疗性或有害有争议的，强调了对良好控制的研究的必要性，从而产生了从特定的大麻素，大脑区域和中枢神经系统细胞类型。我们的研究表明，细胞类型特异性表观遗传学与PLWH中与HIV相关的认知障碍有关的模式，更频繁或最近使用大麻可能减少PLWH中的髓样注射和影响大脑结构，以及我们最近对CNS的单细胞研究在PLWH中显示出不同的CSF小胶质细胞样细胞，在PLWH和正在进行的HIV病毒中表达CD204 脑脊液细胞目的地艺术中的转录。先前的研究表明神经源性大脑区域包括外侧心室和海马的室内室内区域与持续 HIV感染和大麻素暴露。但是，了解神经源性大脑区域的关键差距在HIV和大麻素暴露环境中，单细胞水平仍然存在。我们正在利用大脑组织在非人类灵长类动物（NHP）HIV模型中，已建立的大麻二酚和THC的口服剂量模型，新的单细胞技术的应用，允许同时分析基因表达和开放来自同一细胞的染色质（10倍基因组学多组：RNA+ATAC），这是一种新的单细胞分析能够测量多个Hisstone修改，以及当前艺术方案的药物分析和脑组织中的大麻素水平。我们的中心假设是大麻素在改善中的治疗作用通过增强神经祖细胞和未成熟的神经元并减少神经胶质注射。鉴定细胞类型，表观遗传细胞态和基因与神经病发生，病毒持续性和大麻素暴露有关的途径，我们正在利用180 来自大麻二酚（CBD）或Δ9-的脑组织样品 NHP和单细胞分析中的四氢大麻酚（THC）（10倍基因组学多核和新的在NYGC上开发的单细胞测定能够测量多个组蛋白的基因组存在修饰和蛋白-DNA结合位点）。此外，将从基于HIV状况（+/-）和大麻暴露（+/-）。我们还将探讨单个细胞在神经源性区域的频率通过利用生物信息学管道来检测两者病毒转录本和转座酶可访问的病毒。该项目将产生全面的单元格 NHP和人类中的数据集，以提高我们对艾滋病毒和大麻素之间交叉谈话的理解大脑的神经源性区域，对焦焦计划扩展的目标具有很高的计划优先级。