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.

摘要 尽管引入了联合抗逆转录病毒治疗（cART），中枢神经系统（CNS） 疾病仍然是艾滋病毒患者面临的重大挑战。海洛因等毒品的滥用与 治疗不依从、病毒传播风险更大、HIV临床进展更快 疾病本项目背后的首要假设是， 神经元和神经胶质细胞将揭示艾滋病毒和艾滋病毒与 海洛因滥用，导致认知障碍和抑郁症。他们的身份将指向变革 关于神经艾滋病发病机制的新机制假说，并因此涉及新的治疗靶点， 改善HIV感染者的神经心理功能。 为了检验目前的假设，我们建议使用经过验证的系统生物学策略进行重建 和使用基因谱的基因组规模的整合基因调控网络（相互作用组）的询问， 以最先进的方法对HIV-1转基因（Tg）和野生型大鼠进行RNA测序（RNA-Seq）， 在长期使用（LgA）条件下自愿静脉内药物自我给药，导致依赖性 海洛因摄入量，和短期访问（ShA）的条件，其特点是非依赖性，更 “消遣性”吸食海洛因由于神经胶质细胞在神经元损伤的发病机制中的关键作用， 在神经艾滋病以及滥用药物引起的神经炎症过程中的功能障碍 如阿片类药物，对于所提出的相互作用组，我们将分析神经元、星形胶质细胞和小胶质细胞， 从涉及HIV和药物作用的关键脑区进行荧光激活细胞分选（FACS） 依赖我们将询问相互作用组，以确定基因网络失调驱动的 艾滋病毒与依赖性和非依赖性海洛因摄入的相互作用。具体的机制假设推导 将用病毒载体介导的过表达或 下调和转基因的大鼠和小鼠与额外的基因轮 表达谱分析、行为分析和神经病理学分析，以阐明它们对 HIV和海洛因对认知、抑郁样行为和神经退行性变的影响。 中枢神经系统（CNS）疾病仍然是艾滋病毒流行的一个紧迫问题，尽管 CART的引入注射药物使用与治疗不依从性相关，病毒感染风险更大 传播，以及更快的艾滋病毒疾病的临床进展。目前的建议将带来一个 系统生物学方法，以确定和测试新的机制假设，可能会导致新的 变革性的治疗概念，以改善艾滋病毒感染者的神经心理功能。