Single nucleus gene expression in moderate and compulsive opioid self-administration in a rodent model of HIV

HIV啮齿动物模型中度和强迫性阿片类药物自我给药的单核基因表达

• 批准号: 10682961
• 负责人: PIETRO P SANNA
• 金额: $ 134.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682961
• 关键词: Abstinence; Address; Adopted; Alzheimer' s Disease; Animal Model; Astrocytes; Automobile Driving; Behavior; Behavioral Paradigm; Binding; Brain region; Cell Nucleus; Cells; Central Nervous System; Chronic; Clinical; Complement; Computing Methodologies; Consultations; DSM-IV; Data; Data Coordinating Center; Dependence; Development; Disease; Disease Progression; Dissection; Drug Addiction; Drug abuse; Drug usage; Fentanyl; Freezing; Funding; Gene Expression; General Population; Genes; Genomics; HIV; HIV Infections; HIV-1; Head; Heroin; Human; Impaired cognition; Individual; Intake; Intravenous; Lymphocyte; Macrophage; Malignant Neoplasms; Methamphetamine; Methods; Microglia; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Motivation; National Institute of Drug Abuse; Negative Reinforcements; Nerve Degeneration; Neuroglia; Neurons; Neuropathogenesis; Neuropsychology; Neurosciences; Opioid; Oxycodone; Pathogenesis; Pathogenicity; Pattern; Persons; Pharmaceutical Preparations; Proteins; Rat Transgene; Rattus; Recording of previous events; Recreation; Regulator Genes; Research Personnel; Resources; Risk; Rodent Model; Sampling; Self Administration; Source; Substance Use Disorder; Substance abuse problem; Synapses; Systems Biology; Testing; Therapeutic; Tissues; Transcript; Transgenes; Transgenic Organisms; Virus; cell type; comorbidity; design; drug mechanism; experience; gene network; gene regulatory network; genetic signature; genome-wide; human model; improved; negative emotional state; nerve injury; neuroAIDS; neuroinflammation; new therapeutic target; non-compliance; novel therapeutics; opioid abuse; opioid injection; opioid use; opioid use disorder; prevent; programs; public health relevance; public repository; reconstruction; single cell analysis; single nucleus RNA-sequencing; synergism; therapeutic target; therapeutically effective; transcriptome sequencing; transcriptomics; validation studies; viral transmission

Summary The abuse of opioid drugs is associated with treatment non-compliance, greater risk of viral transmission, and more rapid clinical progression of HIV disease. The overarching hypothesis behind the present project is that the analysis of molecular profiles of neuronal and glia cells at the single cell level in drug abuse-relevant brain regions by single nucleus RNA-Seq (snRNA-Seq) will reveal key genes that are dysregulated by the interaction of HIV with opioid abuse, resulting in neurodegeneration and cognitive impairment. To test the present hypothesis, we propose to use validated systems biology strategies for the reconstruction and interrogation of a genome-scale integrated gene regulatory network in conjunction with snRNA-Seq from HIV transgenic (Tg) rats, which harbor a non-replicating HIV-1 transgene expressing chronic low-levels of multiple HIV-1 proteins in disease-relevant cell types, and wild-type rats. The occasional but limited use of a drug is clinically distinct from dependent drug use, which is characterized by the emergence of dependence and a negative emotional state when access to the drug is prevented that drives negative reinforcement, a powerful source of motivation for drug seeking. Therefore, we will use a state-of-the-art paradigm of voluntary intravenous opioid self-administration under short access (ShA) conditions, which is characterized by a non-dependent, “recreational” pattern of drug use, and long access (LgA) conditions, which leads to dependent drug intake. Escalated drug intake under LgA conditions is highly relevant to human substance use disorder (SUD) as it has been suggested that it models all 7 of the criteria for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and 7 of the 11 criteria in the DSM-V. We showed that HIV Tg rats self-administering oxycodone in this LgA paradigm of escalated self-administration display increased neural injury and cognitive impairment. The project will address the following vexing question about opioid abuse in the setting of HIV infection: what are the cell types and cell states that drive neuroinflammation, neurodegeneration, virus expression, and escalated (dependent) opioid self-administration and cognitive impairment in the setting of HIV? Overall, this collaborative interdisciplinary proposal integrating single cell level transcriptomics, state-of-the- art behavior methods in HIV Tg and wild-type rats, and computational strategies for the deconvolution of the gene regulatory network at the single cell level will elucidate key mechanisms that underlie the effects of HIV and opioid abuse and their detrimental interactions on neuroHIV progression, virus expression and persistence. The results will indicate transformative new mechanistic hypotheses that may lead to novel therapeutic concepts for opioid use disorder (OUD) in the setting of HIV and will establish key resources for the neuroHIV field to be made publicly available through the SCORCH data coordination center and other public repositories.

概括 滥用阿片类药物与治疗不合规，更大的病毒传播风险有关， 以及更快的HIV疾病临床进展。本项目背后的总体假设是 在与药物滥用相关的单细胞水平上神经元和神经胶质细胞分子谱的分析 单核RNA-Seq（SnRNA-Seq）的大脑区域将揭示由失调的关键基因 艾滋病毒与阿片类药物滥用的相互作用，导致神经退行性和认知障碍。测试 目前的假设，我们建议使用经过验证的系统生物学策略进行重建和 与HIV的SnRNA-Seq结合的基因组级综合基因调节网络的询问 转基因（TG）大鼠，其具有非复制的HIV-1转基因表达多重的慢性低水平 与疾病相关的细胞类型和野生型大鼠中的HIV-1蛋白。 偶尔但使用有限的药物使用在临床上与依赖的药物使用不同，即 当吸毒的机会是依赖的出现和负面情绪状态的特征 阻止这驱动负面增强，这是寻求毒品的有力动机。因此，我们 将使用最先进的自愿静脉注射阿片类药物自我管理的范式 （SHA）条件，其特征是非依赖性的“娱乐性”药物使用模式，并且很长 进入（LGA）条件，导致依赖药物摄入。在LGA条件下升级的药物摄入量是 与人类药物使用障碍（SUD）高度相关，因为它已经提出了所有7个模型 诊断和统计手册中的药物成瘾标准（DSM） - IV和11个中的7个 DSM-V中的标准。我们表明，在这种LGA范式中，HIV TG大鼠自我辅助羟考酮 升级的自我管理显示出增加神经损伤和认知障碍。 该项目将在艾滋病毒感染的情况下解决以下有关阿片类药物滥用的问题： 驱动神经炎症，神经变性，病毒表达和细胞状态的细胞类型和细胞状态是什么 在艾滋病毒的情况下，（依赖）阿片类药物的自我管理和认知障碍？ 总体而言，这项合作跨学科建议整合了单细胞级转录组学，最新的 艾滋病毒和野生型大鼠中的艺术行为方法，以及对反卷积的计算策略 单细胞水平的基因调节网络将阐明艾滋病毒影响的基础的关键机制 Oioid滥用及其在神经hiv进展，病毒表达和的有害相互作用 持久性。结果将表明可能导致新颖的新机械假设 阿片类药物使用障碍（OUD）的治疗概念（OUD）在艾滋病毒的环境中，将建立关键资源 通过烧焦数据协调中心和其他公众公开提供的Neurohiv领域 存储库。