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.

概括与HIV相关的神经认知障碍（手）和滥用药物合并症仍然普遍存在尽管抗逆转录病毒疗法（CART）。艾滋病治疗发展领域的主要挑战是识别艾滋病毒感染中持续性神经元功能障碍的目标机制尽管有艺术。尽管内部RNA修饰已知数十年，但它们在RNA代谢和函数才开始阐明。特别是，动态RNA修饰被认为是代表基因表达的新层。本提案将检验总体假设理解RNA修饰在实施基因表达程序中的作用因神经元，星形胶质细胞和小胶质细胞中的艾滋病毒，推车和药物滥用的相互作用而失调，可以表明对神经辅助发病机理的变革性新机械假设，该假设有可能导致确定新型治疗靶点，以改善患有患者的神经心理功能艾滋病病毒。 RNA修饰对HIV TG大鼠HIV转录本，剪接和HIV蛋白水平的影响将也可以调查。为了检验目前的假设，我们组建了一个合作团队，涉及行为方面的专业知识和分子神经生物学，基因表达和先进的系统生物学方法研究转录，转录后和翻译后调节机制。特别是，我们将探索中等或中等的行为范式中的RNA修改在组合的情况下，在HIV转基因（TG）大鼠中强迫性（依赖）可卡因自我给药抗逆转录病毒疗法（CART）。我们将与RNA分析一起使用系统生物学方法确定了脑细胞类型，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辅助。我们将主要关注最丰富的mRNA修饰，N6-甲基读二氨酸（M6A）和构成其调节机械的蛋白质。可卡因摄入量和购物车历史对M6A的影响还将研究HIV TG大鼠中HIV转录本的修饰。确定的机制也将是在中等和强迫性自我给药的其他药物中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，该建议 - 基因网络调节的计算分析界面和先进的行为药理学 - 旨在识别可能的新可检验的机械假设导致变革性的新治疗概念，以改善艾滋病毒患者的神经心理功能。