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

基本信息

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
项目类别：
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

项目摘要

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.

概括 HIV 相关神经认知障碍 (HAND) 和药物滥用合并症仍然普遍存在尽管进行了联合抗逆转录病毒治疗（cART）。艾滋病治疗开发领域的重大挑战是识别 HIV 感染者持续性神经元功能障碍的可靶向机制尽管有艺术，但个人。虽然内部 RNA 修饰几十年前就已为人所知，但它们在 RNA 代谢和的功能才刚刚开始被阐明。特别是，动态 RNA 修饰被认为代表了基因表达的新控制层。本提案将检验总体假设了解 RNA 修饰在基因表达程序实施中的作用 HIV、cART 和神经元、星形胶质细胞和小胶质细胞中药物滥用的相互作用造成失调，可以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确定新的治疗靶点，以改善患者的神经心理功能艾滋病病毒。 RNA修饰对HIV Tg大鼠中HIV转录本和剪接以及HIV蛋白水平的影响将也受到调查。为了检验目前的假设，我们组建了一个协作团队，涉及行为和行为方面的专业知识。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，我们将在中等或中等程度的成熟行为范式中探索 RNA 修饰。 HIV转基因（Tg）大鼠在联合治疗中强迫性（依赖性）可卡因自我给药抗逆转录病毒治疗（cART）。我们将使用系统生物学方法与 RNA 分析相结合确定脑细胞类型以研究 RNA 修饰在神经元损伤和神经胶质细胞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 (m6A) 和组成其调节机制的蛋白质。可卡因摄入史和 cART 对 m6A 的影响还将研究 HIV Tg 大鼠中 HIV 转录物的修饰。确定的机制也将是在中度和强迫性自我给药其他药物模型的后续研究中进行了调查滥用以及可用的人类基因表达数据集。最终这个提议 - 在基因网络调控和计算分析的界面先进的行为药理学 - 旨在确定新的可测试的机制假设，这些假设可能带来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。