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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.

项目总结（摘要）