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：
7292793
负责人：
WALTER ROYAL
金额：
$ 29.11万
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 2012-02-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7292793
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 Kidney Link Lymph Measures Mediating Metabolism Modeling Mononuclear Morphine Nervous system structure Neurologic Neurons Numbers 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 Therapeutic immunosuppression Tissues Toxic effect Transgenes Transgenic Animals Transgenic Organisms Viral Virus Virus Replication Vitamin A Vitamin A Deficiency cognitive function cytokine immune function monocyte mortality nervous system disorder peripheral blood prevent programs promoter receptor expression release factor response tool transgene expression

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转基因大鼠结合了复制缺陷的HIV-1基因组，发展了许多人类HIV疾病的免疫学和临床表现，包括神经系统的参与。 HIV感染中的神经疾病与促炎细胞因子和其他可溶性因子诱导的神经系统组织的损害有关，这些因子被激活的单核细胞释放。已经观察到这些效果在阿片类药物使用者中得到了增强。已经证明类视网膜类似于抑制这种免疫活性，在HIV-1感染的研究中，可以抑制感染的单核细胞系中病毒的复制。维生素A的细胞作用是由特异性结合与视黄酸受体（RAR）和类维生素X受体（RXR）介导的。我们先前已经证明RAR和RXR激活可以通过人细胞系抑制促炎性细胞因子（TNF-A）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作用构成的机制尚不清楚。因此，在这笔赠款中，我们将使用HIV-1转基因大鼠模型检查性类维生素类似的影响。该提案的目的是（1）评估类视视性类动物，拮抗剂和吗啡对HIV-1转基因和对照大鼠体外的单核细胞促炎反应的影响；（2）检查激活和暴露于类维生素性激动剂和拮抗剂以及吗啡对转基因和对照大鼠免疫细胞的MOR表达的影响；（3）检查类视黄素激动剂，拮抗剂和吗啡对转基因和对照大鼠免疫细胞的HIV-1基因表达的影响；（4）检查维生素A缺乏症和吗啡对HIV-1转基因和对照大鼠的临床状况的影响。这些研究将有助于更好地理解性类维生素性代谢和阿片类药物在总体上，更具体地说，在药物使用者中发生神经系统疾病的作用。