Opiate drug abuse and CNS vulnerability to HIV

阿片类药物滥用和中枢神经系统对艾滋病毒的脆弱性

基本信息

批准号：
7686089
负责人：
Kurt F Hauser
金额：
$ 101.71万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7686089
关键词：
Address Apoptotic Astrocytes Cell Culture Techniques Cell Death Cells Cessation of life Corpus striatum structure Dementia Drug abuse Event Free Radicals Genetic Vectors Glutamate Transporter Goals HIV HIV Envelope Protein gp120 HIV encephalitis HIV-1 Heroin Homeostasis Human Immune In Vitro Inflammation Inflammatory Interleukin-6 Knock-out Metabolic Microglia Mitogen-Activated Protein Kinases Mus Nerve Degeneration Neuronal Dysfunction Neurons Opiates Opioid Opioid Receptor Oxidation-Reduction Oxycodone PTEN gene Pathogenesis Pathway interactions Pharmaceutical Preparations Population Process Production Proteins Recombinants SCID Mice Signal Pathway Signal Transduction Transfection Transgenic Mice Transgenic Organisms Viral Viral Core Proteins caspase-3 cytokine endogenous opioids in vivo monocyte multicatalytic endopeptidase complex neurotoxicity overexpression programs

项目摘要

DESCRIPTION (provided by applicant): The goal of the Program Project is to understand how opiate drugs exacerbate the effects of HIV in the CNS. To achieve this goal, we will address the following hypothesis: Opiate drugs, through selective actions at f-opioid receptors (MOR), exacerbate the pathogenesis of HIV-1 by disrupting glial homeostasis, increasing inflammation, and decreasing the threshold for pro-apoptotic events in neurons. Inflammatory processes and viral products released by human immunodeficiency virus type one (HIV-1) infected cells cause widespread metabolic derangement, immune dysregulation, disruption of neuron-glial relationships, and neuronal dysfunction, which contribute to HIV encephalitis and perhaps dementia. Opiate drugs, such as heroin and oxycodone, intrinsically disrupt CNS function, by interfering with endogenous opioid and neuroimmune function. CNS disruption and neurotoxicity are exacerbated when opiates are combined with HIV. Project 1 will examine neurodegenerative mechanisms in opioid and HIV protein-exposed cell cultures and mice. Neuron death and non-lethal effects (e.g., neuritic pruning will be examined in + MOR-expressing populations of striatal neurons in vitro. Signaling between premitochondrial pathways involving PTEN and Akt will be examined for both caspase-3 dependent and independent cell death using pharmacological, transfection (silencing/overexpression vectors) and genetic strategies (MOR-knockout and PTEN-deficient mice). Project 2 will explore opioid and HIV disruption of astroglial function (e.g. Ca2+, oxyradical production, and EAAT1/2 glutamate transporters) and the release of inflammatory cytokines (e.g. TNFa, IL-6) in vitro and in vivo, and will identify aspects of astroglial destabilization that contribute to pathological changes in neurons. Project 3 will examine opioid-HIV-induced changes in free radical production, redox-sensitive intracellular signaling pathways (e.g., proteasome activity/immunoproteasome subunit expression, NFkappaB, MAP kinase) and inflammatory signaling in microglia. Last, studies using conditional transgenic mice expressing Tat or gp120 and severe combined immunodeficient (SCID) mice injected with HIV-infected human monocytes will assess opioid-HIV effects in neurons, astroglia, and microglia in vivo. The Projects are supported by an administrative core (Core A), and a transgenic/SCID mouse core (Core B) and recombinant viral protein core (Core B), and common findings, e.g., on neuronal dysfunction/death will be integrated in Project 1.

描述（由申请人提供）：计划项目的目的是了解鸦片药物如何加剧艾滋病毒在中枢神经系统中的影响。为了实现这一目标，我们将通过F-阿片类受体（MOR）的选择性作用来解决以下假设：阿片类药物，通过破坏神经胶质稳态，增加炎症并减少神经神经元的促进性事件的阈值，加剧HIV-1的发病机理。人类免疫缺陷病毒释放的炎症过程和病毒产物受感染的细胞（HIV-1）感染细胞释放出广泛的代谢危险，免疫失调，神经脱神经关系的破坏以及神经元功能障碍，导致HIV脑炎和痴呆症。阿片类药物（例如海洛因和羟考酮）通过干扰内源性阿片类药物和神经免疫功能来本质上破坏CNS功能。当鸦片与HIV结合时，中枢神经系统的破坏和神经毒性会加剧。项目1将检查阿片类和HIV蛋白暴露的细胞培养物和小鼠中的神经退行性机制。神经元死亡和非致命作用（例如，将在体外表达纹状体神经元的 +表达神经修剪。将在涉及PTEN和AKT的前途径之间检查涉及PTEN和AKT的信号，同时使用药物，转换（Silesical，Sentection and silection and silence and Expecties and Sentection and silenctions and Sentections and Sentections and nor snection and nor snection and nor nor nor nor snection and nor nor snection） PTEN缺乏小鼠）。项目3将检查阿片类HIV诱导的自由基生产的变化，对氧化还原敏感的细胞内信号通路（例如，蛋白酶体活性/免疫蛋白酶体亚基表达，NFKAPPAB，MAP激酶）和使用微胶质细胞中的炎症信号（使用少量小鼠）进行了调节（均具有gp120的疾病）。 HIV-infected human monocytes will assess opioid-HIV effects in neurons, astroglia, and microglia in vivo. The Projects are supported by an administrative core (Core A), and a transgenic/SCID mouse core (Core B) and recombinant viral protein core (Core B), and common findings, e.g., on neuronal dysfunction/death will be integrated in Project 1.

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain.

DOI：
10.1007/s11481-011-9326-z
发表时间：
2012-12
期刊：
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
影响因子：
6.2
作者：
Podhaizer, Elizabeth M.;Zou, Shiping;Fitting, Sylvia;Samano, Kimberly L.;El-Hage, Nazira;Knapp, Pamela E.;Hauser, Kurt F.
通讯作者：
Hauser, Kurt F.

Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death.

DOI：
10.1186/1750-1326-6-78
发表时间：
2011-11-17
期刊：
Molecular neurodegeneration
影响因子：
15.1
作者：
Suzuki M;El-Hage N;Zou S;Hahn YK;Sorrell ME;Sturgill JL;Conrad DH;Knapp PE;Hauser KF
通讯作者：
Hauser KF

Morphine exposure during HIV encephalitis in SCID mice.

DOI：
10.1007/s11064-012-0877-z
发表时间：
2012-12
期刊：
NEUROCHEMICAL RESEARCH
影响因子：
4.4
作者：
Tyor, William R.;Hwang, Hee Young;Fritz-French, Cari
通讯作者：
Fritz-French, Cari

Regional heterogeneity and diversity in cytokine and chemokine production by astroglia: differential responses to HIV-1 Tat, gp120, and morphine revealed by multiplex analysis.

DOI：
10.1021/pr900926n
发表时间：
2010-04-05
期刊：
JOURNAL OF PROTEOME RESEARCH
影响因子：
4.4
作者：
Fitting, Sylvia;Zou, Shiping;Chen, Wen;Vo, Phu;Hauser, Kurt F.;Knapp, Pamela E.
通讯作者：
Knapp, Pamela E.

Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca(2+)](i), NF-kappaB trafficking and transcription.