Systems biology of RNA Modifications in HIV/AIDS and Substance Use Disorders

HIV/艾滋病和药物滥用疾病中 RNA 修饰的系统生物学

• 批准号: 10318620
• 负责人: PIETRO P SANNA
• 金额: $ 65.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318620
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Alcohols; Algorithms; Animal Model; Anti-Retroviral Agents; Astrocytes; Behavioral; Behavioral Paradigm; Biochemical; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cocaine; Computer Analysis; Computing Methodologies; Data Set; Disease; Disease Progression; Down-Regulation; Epidemiology; Follow-Up Studies; Functional disorder; Funding; Gene Expression; Gene Expression Profiling; Genetic; Genetic Transcription; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Heroin; Human; Immunoprecipitation; Impaired cognition; Individual; Intake; Intravenous; Lead; Mediating; Medicine; Mental Depression; Messenger RNA; Methamphetamine; Methods; Methylation; MicroRNAs; Microglia; Modeling; Modification; Molecular; Molecular Neurobiology; Morphology; Motor; National Institute of Drug Abuse; Neurobiology; Neuroglia; Neuroimmune; Neurologic; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropsychology; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Phenotype; Post-Transcriptional Regulation; Post-Translational Regulation; Premature aging syndrome; Proteins; RNA; RNA Splicing; RNA metabolism; Rattus; Recording of previous events; Regulation; Regulator Genes; Research Institute; Research Support; Role; Self Administration; Small Interfering RNA; Substance Use Disorder; Substance abuse problem; Systems Biology; Testing; Therapeutic; Transcript; Transcriptional Regulation; Transgenic Organisms; United States National Institutes of Health; Validation; Viral reservoir; Writing; advanced system; antiretroviral therapy; behavioral pharmacology; brain cell; candidate marker; cell type; cocaine self-administration; college; comorbidity; drug of abuse; epitranscriptomics; gene network; improved; neuroAIDS; neurotoxicity; new therapeutic target; novel therapeutics; overexpression; programs; public health relevance; substance use; therapeutic development; transcriptome; transcriptome sequencing

Summary HIV-associated neurocognitive disorders (HANDs) and substance abuse comorbidity remain prevalent despite combination antiretroviral therapy (cART). A major challenge in the AIDS therapeutic development field is the identification of targetable mechanisms that underlie persistent neuronal dysfunction in HIV-infected individuals despite ART. While internal RNA modifications have been known for decades, their roles in RNA metabolism and function are only beginning to be elucidated. In particular, dynamic RNA modifications are believed to represent a new layer of control of gene expression. The present proposal will test the overarching hypothesis that understanding the role of RNA modifications in the implementation of gene expression programs that are dysregulated by the interaction of HIV, cART and substance abuse in neurons, astrocytes and microglia, can indicate transformative new mechanistic hypotheses on neuroAIDS pathogenesis that will have the potential to lead to the identification of novel therapeutic targets to improve neuropsychological functioning in people with HIV. The impact of RNA modifications on HIV transcripts and splicing and HIV protein levels in HIV Tg rats will also be investigated. To test the present hypothesis we assembled a collaborative team involving expertise in behavioral and molecular neurobiology, gene expression and advanced systems biology methods to study transcriptional, post-transcriptional and post-translational regulatory mechanisms. In particular, we will explore RNA modifications in well-established behavioral paradigms of moderate or compulsive (dependent) cocaine self-administration in HIV transgenic (Tg) rats in the setting of combination antiretroviral therapy (cART). We will use a systems biology approach in conjunction with RNA profiling in identified brain cell types to investigate the role of RNA modifications in neuronal injury and glia dysfunction in neuroAIDS. We will focus primarily on the most abundant mRNA modification, N6-methyladenosine (m6A) and the proteins that compose its regulatory machinery. The effects of histories of cocaine intake and cART on m6A modification of HIV transcripts in HIV Tg rats will also be investigated. The mechanisms identified will also be investigated in follow-up studies in models of moderate and compulsive self-administration of other drugs of abuse as well as available human gene expression datasets. Ultimately this proposal - at the interface of computational analysis of gene network regulation and advanced behavioral pharmacology - is aimed at identifying new testable mechanistic hypotheses that may lead to transformative new therapeutic concepts to improve neuropsychological functioning in people with HIV.

总结 HIV相关的神经认知障碍（HANDs）和药物滥用合并症仍然普遍存在 尽管联合抗逆转录病毒治疗（cART）。艾滋病治疗开发领域的一个重大挑战 是确定HIV感染者持续神经功能障碍的靶向机制， 尽管艺术。 虽然内部RNA修饰已经知道了几十年，但它们在RNA代谢和 功能才刚刚开始被阐明。特别地，动态RNA修饰被认为 代表了基因表达的新控制层。本提案将检验这一总体假设 理解RNA修饰在基因表达程序中的作用， 在神经元、星形胶质细胞和小胶质细胞中，由于HIV、cART和药物滥用的相互作用而失调， 表明关于神经艾滋病发病机制的变革性新机制假说，将有可能 导致识别新的治疗靶点，以改善神经心理功能的人， 艾滋病。RNA修饰对HIV Tg大鼠中HIV转录和剪接以及HIV蛋白水平的影响将 也被调查。 为了验证这个假设，我们组建了一个合作团队， 分子神经生物学，基因表达和先进的系统生物学方法来研究转录， 转录后和翻译后调节机制。 特别是，我们将探讨RNA修饰在成熟的行为范式的中度或 HIV转基因（Tg）大鼠在联合用药环境下的可卡因自我给药强迫（依赖） 抗逆转录病毒疗法（cART）。我们将使用系统生物学方法结合RNA分析， 确定脑细胞类型，以研究RNA修饰在神经元损伤和神经胶质功能障碍中的作用。 神经艾滋病我们将主要关注最丰富的mRNA修饰，N6-甲基腺苷（m6 A）和 组成其调节机制的蛋白质。可卡因摄入史和cART对m6 A的影响 还将研究HIV Tg大鼠中HIV转录物的修饰。所确定的机制还将 在其他药物的中度和强迫性自我给药模型的随访研究中进行了调查， 滥用以及可用的人类基因表达数据集。 最终，这个建议-在基因网络调控的计算分析的界面上， 先进的行为药理学-旨在确定新的可测试的机制假设， 导致变革性的新治疗概念，以改善艾滋病毒感染者的神经心理功能。