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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

总结