Neural substrates of opiate-HIV interactions.

阿片类药物与艾滋病毒相互作用的神经基质。

• 批准号: 9344568
• 负责人: PIETRO P SANNA
• 金额: $ 58.1万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344568
• 关键词: Address; Alcohol or Other Drugs use; Area; Astrocytes; Automobile Driving; Behavior; Behavioral; Brain region; California; Cancer Biology; Cells; Central Nervous System Diseases; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cognitive; Comorbidity; Contracts; Data Set; Disease; Disease Progression; Down-Regulation; Drug Addiction; Drug abuse; Exposure to; Fluorescence-Activated Cell Sorting; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Head; Heroin; Heroin Abuse; Human; Immune; Impaired cognition; Individual; Injury; Intake; Intravenous; Investigation; Lead; Measures; Mediating; Medicine; Mental Depression; Microglia; Modeling; Molecular; Molecular Analysis; Molecular Neurobiology; Molecular Profiling; Mus; National NeuroAids Tissue Consortium; Nerve Degeneration; Neuraxis; Neurobiology; Neuroglia; Neurologic; Neuronal Dysfunction; Neurons; Neuropsychology; Opiates; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Population; Prefrontal Cortex; Premature aging syndrome; Process; Proteins; Rattus; Recording of previous events; Regulator Genes; Research Personnel; Research Priority; Risk; Rodent; Role; Sample Size; Self Administration; Small Interfering RNA; Substance Addiction; Substance of Abuse; Systems Biology; Testing; Therapeutic; Transcript; Transgenic Organisms; Universities; Ursidae Family; Viral Vector; antiretroviral therapy; base; cell type; college; drug of abuse; genome-wide; improved; injection drug use; mutant; neuroAIDS; neuroinflammation; neuropathology; new therapeutic target; non-compliance; novel; overexpression; pandemic disease; public health relevance; reconstruction; relating to nervous system; transcriptome sequencing; viral transmission; virology

Abstract Despite the introduction of combination antiretroviral therapy (cART), central nervous system (CNS) disease remains a significant challenge in patients with HIV. The abuse of drugs such as heroin is associated with treatment non-compliance, greater risk of viral transmission, and more rapid clinical progression of HIV disease. The overarching hypothesis behind the present project is that the analysis of molecular profiles of neuronal and glia cells will reveal key genes that are dysregulated by HIV and by the interaction of HIV with heroin abuse, resulting in cognitive impairments and depression. Their identification will point to transformative new mechanistic hypotheses on neuroAIDS pathogenesis and, consequently, to novel therapeutic targets to improve neuropsychological functioning in people with HIV. To test the present hypothesis, we propose to use validated systems biology strategies for the reconstruction and interrogation of a genome-scale integrated gene regulatory network (interactome) using gene profiles by RNA sequencing (RNA-Seq) from HIV-1 transgenic (Tg) and wild-type rats in a state-of-the-art paradigm of voluntary intravenous drug self-administration under long access (LgA) conditions, which leads to dependent heroin intake, and short access (ShA) conditions, which is characterized by a non-dependent, more “recreational” pattern of heroin use. Because of the pivotal roles of glia cells in the pathogenesis of neuronal dysfunction in the setting of neuroAIDS as well as in neuroinflammatory processes induced by drugs of abuse such as opiates, for the proposed interactome we will profile neurons, astrocytes and microglia purified by fluorescence-activated cell sorting (FACS) from key brain regions involved in the effects of HIV and drug dependence. We will interrogate the interactome to identify the gene network dysregulations driven by the interaction of HIV and dependent and non-dependent heroin intake. Specific mechanistic hypotheses derived from interactome reconstruction and interrogation will be tested with viral vector-mediated overexpression or down-regulation and genetically modified rats and mice in conjunction with additional rounds of gene expression profiling, behavioral analyses and neuropathology analyses to elucidate their contributions to the effects of HIV and heroin on cognition, depression-like behavior, and neurodegeneration. Central nervous system (CNS) disease remains a pressing problem in the HIV pandemic despite the introduction of cART. Injection drug use is associated with treatment non-compliance, greater risk of viral transmission, and more rapid clinical progression of HIV disease. The present proposal will bring to bear a systems biology approach to identify and test new mechanistic hypotheses that may lead to novel transformative therapeutic concepts to improve neuropsychological functioning in people with HIV.

抽象的 尽管引入了联合抗逆转录病毒疗法（cART），中枢神经系统（CNS） 这种疾病对于艾滋病毒患者来说仍然是一个重大挑战，这与海洛因等药物的滥用有关。 治疗不依从、病毒传播风险更大以及艾滋病毒临床进展更快 本项目背后的总体假设是对疾病的分子谱进行分析。 神经元和神经胶质细胞将揭示因 HIV 以及 HIV 与病毒相互作用而失调的关键基因。 海洛因滥用，导致认知障碍和抑郁症，他们的识别将指向变革。 关于神经艾滋病发病机制的新机制假说，从而提出新的治疗靶点 改善艾滋病毒感染者的神经心理功能。 为了检验当前的假设，我们建议使用经过验证的系统生物学策略来重建 以及使用基因图谱对基因组规模的整合基因调控网络（interactome）进行询问 在最先进的范例中对 HIV-1 转基因 (Tg) 和野生型大鼠进行 RNA 测序 (RNA-Seq) 在长通路（LgA）条件下自愿静脉注射药物，这会导致依赖性 海洛因摄入量和短期获取（ShA）条件，其特点是非依赖性、更多 由于神经胶质细胞在神经元发病机制中的关键作用，海洛因使用的“娱乐”模式。 神经艾滋病环境中的功能障碍以及滥用药物引起的神经炎症过程 例如阿片类药物，对于拟议的相互作用组，我们将分析通过纯化纯化的神经元、星形胶质细胞和小胶质细胞 对参与 HIV 和药物影响的关键大脑区域进行荧光激活细胞分选 (FACS) 我们将询问相互作用组以确定由依赖性驱动的基因网络失调。 HIV 与依赖和非依赖海洛因摄入的相互作用。 来自相互作用组重建和询问的结果将通过病毒载体介导的过度表达或 下调和转基因大鼠和小鼠与额外轮次的基因相结合 表达谱、行为分析和神经病理学分析，以阐明它们对 艾滋病毒和海洛因对认知、抑郁样行为和神经变性的影响。 尽管中枢神经系统（CNS）疾病仍然是艾滋病毒大流行中的一个紧迫问题 注射药物的使用与治疗不依从性和更大的病毒风险有关。 传播和艾滋病毒疾病更快的临床进展。 系统生物学方法来识别和测试可能导致新的机制假设 改善艾滋病毒感染者神经心理功能的变革性治疗理念。