Omics Analyses of HIV and Substance Use Disorder

摘要 为了产生关于神经艾滋病毒发病机制和疾病进展的新机制假说 寻找新的治疗靶点以改善HIV感染者的神经心理功能 滥用共病和神经退行性疾病，这项提议将利用融合的最先进的Omics 策略包括转录、表位转录和蛋白质组学。具体地说，我们将进行基因 以CART为代表的HIV患者和对照组额叶皮质RNA-Seq的表达谱 有和没有依赖物质滥用史的ERA临床表现 国家神经艾滋病组织联盟(NNTC)。我们将带来一个系统生物学框架来 产生机械假说，在初步研究中允许我们确定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(M6A)RNA甲基化代表了宿主基因表达的额外一层 神经性艾滋病毒和阿尔茨海默病的潜在致病意义。特别是，初步结果 提示HIV诱导转录本m6A甲基化改变，涉及与以下相关的途径 突触树突状细胞损伤和神经变性、炎症和RNA加工，从而导致m6A RNA甲基化 还将进行概况分析。信号分子一氧化氮(NO)的过度产生导致 蛋白质S-亚硝化，一种与衰老、神经退行性疾病有关的翻译后修饰， 包括阿尔茨海默氏症和帕金森氏症，以及神经性艾滋病毒。我们的初步数据显示结果是一致的 来自基因表达和S亚硝基蛋白质组学的分析。因此，我们将整合转录组 用质谱仪对S亚硝基蛋白质组进行蛋白质组学分析。总而言之，这些研究将 应用集成的OMICS方法，包括对宿主艾滋病毒监管鲜为人知的和正在出现的方面 相互作用，如RNA甲基化和蛋白质亚硝化在系统生物学框架中生成 机械假说，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的神经心理功能，药物滥用共病和 神经退行性疾病。

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.