Omics Analyses of HIV and Substance Use Disorder

HIV 和药物滥用障碍的组学分析

• 批准号: 10448502
• 负责人: Vez REPUNTE-CANONIGO
• 金额: $ 85.44万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448502
• 关键词: Aging; Alzheimer' s Disease; Area; Automobile Driving; Behavioral; Biochemical; Clinical; Data; Disease Progression; Dissection; Drug abuse; Environment; Gene Expression; Gene Expression Profiling; Grant; HIV; HIV-associated neurocognitive disorder; Human; Huntington Disease; In Vitro; Individual; Inflammation; Injury; Integration Host Factors; Literature; Lymphocyte; Mass Spectrum Analysis; Messenger RNA; Methods; Methylation; MicroRNAs; Microglia; Modification; Molecular; Morphology; National NeuroAids Tissue Consortium; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropsychology; Nitric Oxide; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Play; Post-Translational Protein Processing; Production; Protein S; Proteins; Proteomics; RNA; RNA Processing; RNA methylation; Rattus; Recording of previous events; Regulation; Regulator Genes; Role; Sampling; Signaling Molecule; Substance Use Disorder; Substance abuse problem; System; Systems Biology; Testing; Transcript; Transgenic Organisms; Ursidae Family; Validation; Virus; behavioral phenotyping; cell type; comorbidity; disease classification; druggable target; effective therapy; epitranscriptomics; frontal lobe; gene network; gene regulatory network; improved; in vivo; miRNA expression profiling; multidisciplinary; neuroAIDS; new therapeutic target; novel; novel therapeutics; oxidative damage; programs; public health relevance; reactivation from latency; stimulant abuse; transcriptome sequencing; transcriptomics

Summary In order to generate new mechanistic hypotheses on neuroHIV pathogenesis and disease progression to identify novel therapeutic targets to improve neuropsychological functioning in people with HIV, substance abuse comorbidity and neurodegenerative diseases, this proposal will utilize convergent state-of-the-art Omics strategies including transcriptomic, epitranscriptomic and proteomics. Specifically, we will carry out gene expression profiles by RNA-Seq from the frontal cortex of HIV+ patients and controls representative of cART era clinical presentations with and without histories of dependent substance abuse from samples of the National NeuroAIDS Tissue Consortium (NNTC). We will bring to bear a systems biology framework to generate mechanistic hypotheses that in preliminary studies allowed us to identify candidate drivers of gene expression changes associated with neuroHIV and neurodegenerative diseases including Alzheimer’s and Huntington’s diseases. The scientific literature together with our preliminary results, indicate that N6- methyladenosine (m6A) RNA methylation represents an additional layer of host gene expression of great potential pathogenic significance in both neuroHIV and Alzheimer’s disease. In particular, preliminary results indicate that HIV induces altered m6A methylation of transcripts involved in pathways related to synaptodendritic injury and neurodegeneration, inflammation and RNA processing, thus m6A RNA methylation profiling will also be carried out. Excessive production of the signaling molecule nitric oxide (NO) leads to protein S-nitrosylation, a posttranslational modification associated with aging, neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, and neuroHIV. Our preliminary data show convergent results from analyses of gene expression and S-nitrosoproteomics. Therefore, we will integrate the transcriptomics with Mass Spectrometry (MS) proteomic analysis of the S-nitrosoproteome. In summary, these studies will apply an integrated Omics approach including little understood and emerging aspects of host-HIV regulatory interactions, such as RNA-methylation and protein nitrosylation in a systems biology framework to generate mechanistic hypotheses that will be tested in the second part of the grant to identify novel therapeutic concepts to improve neuropsychological functioning in people with HIV, substance abuse comorbidity and neurodegenerative diseases.

总结 为了产生关于neuroHIV发病机制和疾病进展的新机制假说， 确定新的治疗靶点，以改善艾滋病毒感染者的神经心理功能， 滥用并发症和神经退行性疾病，该提案将利用融合的最先进的组学 包括转录组学、表转录组学和蛋白质组学。具体来说，我们将进行基因 来自HIV+患者和对照的额叶皮质的代表cART的RNA-Seq表达谱 era临床表现，有和没有依赖性物质滥用的历史，从样本的 国家神经艾滋病组织联盟（NNTC）。我们将提出一个系统生物学框架， 产生机制假设，在初步研究中，使我们能够识别基因的候选驱动因素 与神经HIV和神经退行性疾病相关的表达变化，包括阿尔茨海默病和 亨廷顿氏病。科学文献和我们的初步结果表明，N6- 甲基腺苷（m6 A）RNA甲基化代表了宿主基因表达的另一层， 在神经艾滋病毒和阿尔茨海默病中具有潜在的致病意义。特别是初步结果 这表明HIV诱导了转录物m6 A甲基化的改变，这些转录物参与了与以下相关的途径： 突触树突损伤和神经变性，炎症和RNA加工，从而m6 A RNA甲基化 还将进行特征分析。信号分子一氧化氮（NO）的过量产生导致 蛋白S-亚硝基化，一种与衰老、神经变性疾病 包括阿尔茨海默氏症和帕金森氏症，以及神经艾滋病。我们的初步数据显示， 从基因表达和S-亚硝基蛋白质组学的分析。因此，我们将整合转录组学 用质谱（MS）对S-亚硝基蛋白质组进行蛋白质组学分析。总之，这些研究将 应用综合组学方法，包括对宿主-HIV调节的知之甚少和新兴方面 相互作用，如RNA甲基化和蛋白质亚硝基化在系统生物学框架，以产生 机制假设，将在赠款的第二部分进行测试，以确定新的治疗概念 改善艾滋病毒感染者、药物滥用合并症患者和 神经退行性疾病