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Opoid and Retinoid Interactions in the HIV-1 Transgenic Rat

HIV-1 转基因大鼠中阿片和类视黄醇的相互作用

基本信息

批准号：
8271939
负责人：
WALTER ROYAL
金额：
$ 0.4万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8271939
关键词：
A-factor (Streptomyces)Agonist Animal Model Animals Binding Blood Blood Cells Cell Line Cell physiology Cells Clinical Clinical Trials Control Animal Development Disease Disease Progression Drug user Exposure to Gene Expression Genome Grant HIV HIV Envelope Protein gp120 HIV Infections HIV Receptors HIV-1 Human Human Cell Line Illicit Drugs Immune Immunity Immunosuppression Impaired cognition Implant In Vitro Individual Infection Inflammatory Injection of therapeutic agent Interferons Kidney Link Lymph Measures Mediating Metabolism Modeling Mononuclear Morphine Nervous system structure Neurologic Neurons Opioid Opioid Receptor Organ Pathogenesis Peripheral Persons Pharmaceutical Preparations Production Progressive Disease Proteins RXR Rattus Receptor Activation Recording of previous events Research Personnel Retinoic Acid Receptor Retinoid Receptor Retinoids Role Sampling Skin Spleen Substance of Abuse Supplementation T-Lymphocyte TNF gene Tissues Toxic effect Transgenes Transgenic Animals Transgenic Organisms Viral Virus Virus Replication Vitamin A Vitamin A Deficiency cognitive function cytokine env Genes immune function monocyte mortality mu opioid receptors nef Genes nervous system disorder peripheral blood prevent programs promoter receptor expression release factor response tat Genes tool transgene expression vif Genes

项目摘要

DESCRIPTION (provided by applicant): The HIV-1 transgenic rat, which incorporates a replication-defective HIV-1 genome, develops a number of the immunological and clinical manifestations of human HIV disease, including nervous system involvement. Neurological disease in HIV infection has been associated with damage to nervous system tissue induced by proinflammatory cytokines and other soluble factors that are released by activated mononuclear cells. These effects have been observed to be enhanced in opioid users. Retinoids have been demonstrated to suppress such immune activity, and, in studies of HIV-1 infection, can suppress replication of virus in infected mononuclear cell lines. The cellular effects of vitamin A are mediated by specific binding to retinoic acid receptor (RAR) and retinoid X receptor (RXR). We have previously demonstrated that RAR and RXR activation can suppress proinflammatory cytokine (TNF-a) production by human cell lines and that morphine can inhibit RXR-mediated TNF-a suppression. RXR activation also increased mu opioid receptor (MOR) expression. The clinical implications of these observations and the mechanisms that underlie these effects are unclear. Therefore, in this grant we will examine the effects of retinoids using the HIV-1 transgenic rat model. The aims of this proposal are to (1) To assess the effects of retinoid agonists and antagonists and morphine on proinflammatory responses by mononuclear cells from the HIV-1 transgenic and control rats in vitro; (2) To examine the effects of activation and exposure to retinoid agonists and antagonists and morphine on MOR expression by immune cells from transgenic and control rats; (3) To examine the effects of retinoid agonists and antagonists and morphine on HIV-1 gene expression by immune cells from transgenic and control rats; and (4) To examine the effects of vitamin A deficiency and morphine on the clinical status of HIV-1 transgenic and control rats. These studies will be useful for better understanding the role of retinoid metabolism and opioids in the pathogenesis of HIV infection in general and, more specifically, in the occurrence of nervous system disease in drug users.

描述（由申请人提供）：HIV-1转基因大鼠含有复制缺陷型HIV-1基因组，会出现人类HIV疾病的许多免疫学和临床表现，包括神经系统受累。 HIV感染引起的神经系统疾病与促炎细胞因子和激活的单核细胞释放的其他可溶性因子引起的神经系统组织损伤有关。据观察，这些作用在阿片类药物使用者中会增强。类维生素A已被证明可以抑制这种免疫活性，并且在HIV-1感染的研究中，可以抑制病毒在受感染的单核细胞系中的复制。维生素 A 的细胞作用是通过与视黄酸受体 (RAR) 和类视黄醇 X 受体 (RXR) 的特异性结合介导的。我们之前已经证明，RAR 和 RXR 激活可以抑制人类细胞系促炎细胞因子 (TNF-a) 的产生，并且吗啡可以抑制 RXR 介导的 TNF-a 抑制。 RXR 激活还增加了 mu 阿片受体 (MOR) 的表达。这些观察结果的临床意义以及这些影响的机制尚不清楚。因此，在这笔资助中，我们将使用 HIV-1 转基因大鼠模型检查类视黄醇的作用。该提案的目的是（1）在体外评估类维生素A激动剂和拮抗剂以及吗啡对来自HIV-1转基因大鼠和对照大鼠的单核细胞促炎反应的影响； (2) 检测激活和暴露于类维生素A激动剂和拮抗剂以及吗啡对转基因和对照大鼠免疫细胞MOR表达的影响； (3) 检测类维生素A激动剂和拮抗剂以及吗啡对转基因大鼠和对照大鼠免疫细胞HIV-1基因表达的影响； (4) 研究维生素A缺乏和吗啡对HIV-1转基因大鼠和对照大鼠临床状态的影响。这些研究将有助于更好地了解类维生素A代谢和阿片类药物在艾滋病毒感染发病机制中的作用，更具体地说，在吸毒者神经系统疾病发生中的作用。