Omics Analyses of HIV and Substance Use Disorder

HIV 和药物滥用障碍的组学分析

基本信息

批准号：
10666424
负责人：
Vez REPUNTE-CANONIGO
金额：
$ 83.6万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
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/10666424
关键词：
Aging Alzheimer&apos s Disease Area Automobile Driving Behavioral Biochemical Central Nervous System Clinical Data Dimensions Disease 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 Maps Mass Spectrum Analysis Messenger RNA Methods Methylation MicroRNAs Microglia Modification Molecular Morphology National NeuroAids Tissue Consortium Nerve Degeneration 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 Rat Transgene Recording of previous events Regulation Regulator Genes Role Sampling Signaling Molecule Substance Use Disorder Substance abuse problem System Systems Biology Testing Transcript Validation Virus behavioral phenotyping candidate identification 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

项目摘要

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.

概括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设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合并症和神经退行性疾病，该提案将利用最先进的融合组学策略包括转录组学、表观转录组学和蛋白质组学。 HIV+ 患者和代表 cART 对照的额叶皮质的 RNA-Seq 表达谱时代临床表现，有或没有依赖性药物滥用史，来自样本国家神经艾滋病组织联盟 (NNTC) 我们将采用系统生物学框架。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艾滋病毒和神经退行性疾病（包括阿尔茨海默病）相关的表达变化亨廷顿舞蹈病。科学文献和我们的初步结果表明，N6- 甲基腺苷 (m6A) RNA 甲基化代表宿主基因表达的附加层在神经艾滋病毒和阿尔茨海默病中潜在的致病意义特别是初步结果。表明 HIV 诱导与相关途径相关的转录物 m6A 甲基化发生改变突触树突损伤和神经变性、炎症和 RNA 加工，从而导致 m6A RNA 甲基化信号分子一氧化氮 (NO) 的过量产生也将进行。蛋白质 S-亚硝基化，一种与衰老、神经退行性疾病相关的翻译后修饰，包括阿尔茨海默病、帕金森病以及神经艾滋病毒。我们的初步数据显示了趋同的结果。因此，我们将整合转录组学。总之，这些研究将通过质谱（MS）对 S-亚硝基蛋白质组进行蛋白质组学分析。应用综合组学方法，包括宿主艾滋病毒监管鲜为人知和新兴的方面相互作用，例如系统生物学框架中的RNA甲基化和蛋白质亚硝基化，以生成将在拨款的第二部分中测试机制假设，以确定治疗新概念改善艾滋病毒、药物滥用合并症和神经退行性疾病。