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

HIV啮齿动物模型中度和强迫性自我给药的单核基因表达

• 批准号: 10454706
• 负责人: PIETRO P SANNA
• 金额: $ 133.83万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454706
• 关键词: Address; Adopted; Alzheimer' s Disease; Animal Model; Astrocytes; Automobile Driving; Behavior; Behavioral Paradigm; Binding; Brain region; Cell Nucleus; Cells; Chronic; Clinical; Computing Methodologies; Contracts; DSM-IV; DSM-V; Data; Data Coordinating Center; Development; Disease; Disease Progression; Drug Addiction; Drug usage; Freezing; Gene Expression; Genes; Genomics; Goals; HIV; HIV Infections; HIV-1; Head; Human; Impairment; Intake; Intravenous; Lead; Lymphocyte; Malignant Neoplasms; Methamphetamine; Methamphetamine use disorder; Methods; Microglia; Modeling; Molecular; Nerve Degeneration; Neuraxis; Neurons; Neuropathogenesis; Neuropsychology; Neurosciences; Pathogenicity; Pathway Analysis; Patients; Pattern; Persons; Pharmaceutical Preparations; Proteins; Rat-1; Rattus; Recording of previous events; Regulation; Regulator Genes; Research Personnel; Resolution; Resources; Rodent Model; Sampling; Self Administration; Small Nuclear RNA; Substance Use Disorder; Synapses; Systems Biology; Testing; Therapeutic; Tissues; Transcript; Transgenes; Transgenic Organisms; Ursidae Family; Validation; Virus; cell type; comorbidity; drug mechanism; experience; gene network; gene regulatory network; genetic signature; genome-wide; high throughput analysis; improved; macrophage; methamphetamine abuse; methamphetamine effect; methamphetamine use; nerve injury; neuroAIDS; neuroinflammation; new therapeutic target; novel; novel therapeutics; public health relevance; reconstruction; relating to nervous system; single cell analysis; stimulant abuse; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics; validation studies

Summary The abuse of stimulants such as methamphetamine (METH) exacerbates the deleterious effects of HIV infection. Here, we will carry out single nucleus RNA-Seq with the goal of identifying cell types and cell states that are pivotal in the effects of HIV and chronic methamphetamine (METH) self-administration on key brain regions relevant to the effects of persistent HIV infection and METH use disorder in HIV transgenic (Tg) rats, which harbor a non-replicating HIV-1 transgene and express chronic low-levels of multiple HIV-1 proteins. The occasional but limited use of a drug is clinically distinct from escalated drug use, which is characterized by the emergence of chronic compulsive drug-seeking and taking. Thus, we will use an established, state-of-the-art paradigm of voluntary intravenous drug self-administration under long access (LgA) conditions that leads to escalated (compulsive) METH intake in comparison to self-administration under short access (ShA) conditions, which leads to a moderate and stable pattern of METH intake. The paradigm of escalated drug intake under LgA conditions is highly relevant to the human substance use disorder (SUD) as 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 METH in this paradigm display increased compulsivity, neuroinflammation, and neural injury. The project will address the following vexing question about persistent HIV infection in the CNS: what are the cell types and cell states that drive neuroinflammation, neurodegeneration, and compulsive METH abuse in the setting of HIV that can reveal the pathogenic mechanisms behind neuroHIV disease progression, virus expression and persistence? The overarching hypothesis behind the present project is that the exploration of the gene regulatory network at the single cell level will elucidate key mechanisms that underlie the effects of HIV and METH abuse and their detrimental interactions on neuroHIV disease progression, virus expression, and virus persistence and will indicate novel therapeutic targets for neuroinflammation, neurodegeneration, and compulsivity to take METH. To test this hypothesis, we will use a validated systems biology strategy for the reconstruction and interrogation of genome-wide gene regulatory networks to identify the gene network dysregulations associated with the effects of HIV, compulsive METH use, and their interactions at single cell resolution gene profiling by single nucleus RNA-Seq. 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 is expected to identify novel mechanistic hypotheses that may lead to transformative new therapeutic concepts for substance use disorder (SUD) in the HIV setting, and will establish key resources for the neuroHIV field to be made publicly available through the SCORCH data coordination center.

概括 滥用甲基苯丙胺 (METH) 等兴奋剂会加剧艾滋病毒的有害影响 感染。在这里，我们将进行单核 RNA-Seq，目的是识别细胞类型和细胞状态 HIV 和慢性甲基苯丙胺 (METH) 自我给药对关键大脑的影响至关重要 与艾滋病毒转基因（Tg）大鼠中持续艾滋病毒感染和冰毒使用障碍的影响相关的区域， 它含有非复制型 HIV-1 转基因，并长期表达低水平的多种 HIV-1 蛋白。这 偶尔但有限地使用药物在临床上与逐步增加的药物使用不同，后者的特点是 出现慢性强迫性寻药和吸毒现象。因此，我们将使用一个成熟的、最先进的 在长通路（LgA）条件下自愿静脉注射药物自我给药的范例，导致 与短时间（ShA）条件下的自我管理相比，METH 摄入量增加（强迫性）， 这导致冰毒摄入量适度且稳定。药物摄入量递增的范式 LgA 状况与人类物质使用障碍 (SUD) 高度相关，因为它模拟了所有 7 个标准 《精神疾病诊断与统计手册》(DSM)-IV 中针对药物成瘾的规定以及 11 项标准中的 7 项 在 DSM-V 中。我们发现，在这种范式中，HIV Tg 大鼠自我施用 METH 的效果增加 强迫症、神经炎症和神经损伤。该项目将解决以下令人烦恼的问题： 中枢神经系统中持续的艾滋病毒感染：驱动神经炎症的细胞类型和细胞状态是什么？ 神经退行性变，以及艾滋病毒背景下强迫性滥用冰毒，可以揭示致病因素 神经艾滋病毒疾病进展、病毒表达和持久性背后的机制？首要的 本项目背后的假设是探索单细胞的基因调控网络 水平将阐明艾滋病毒和冰毒滥用及其有害影响的关键机制 神经艾滋病毒疾病进展、病毒表达和病毒持久性之间的相互作用，并将表明新的 神经炎症、神经变性和强迫性服用冰毒的治疗目标。为了测试这个 假设，我们将使用经过验证的系统生物学策略来重建和询问 全基因组基因调控网络，以确定与效应相关的基因网络失调 HIV、强迫性冰毒使用及其在单细胞分辨率基因分析中的相互作用（单核） RNA测序。总体而言，这一跨学科协作提案整合了单细胞水平转录组学， HIV Tg 和野生型大鼠中最先进的行为方法和计算策略预计将 确定新的机制假设，这些假设可能会导致物质的变革性新治疗概念 在艾滋病毒环境中使用障碍（SUD），并将为神经艾滋病毒领域建立关键资源 通过 SCORCH 数据协调中心公开可用。