MODULATION OF ONCOGENIC AGENTS BY MARIJUANA

大麻对致癌物质的调节

基本信息

批准号：
7939347
负责人：
PETER Gabor MEDVECZKY
金额：
$ 9.78万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7939347
关键词：
Acquired Immunodeficiency Syndrome Acute Acyclovir Aging Agonist Animal Model Antiviral Agents Area B-Lymphocytes Binding Biochemical Biological Assay Breast Carcinoma CNR1 gene CNR2 gene CREB-binding protein Cannabinoids Carcinogens Cell Line Cell Nucleus Cell physiology Cell surface Cells Computer Systems Development Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein DNA Data Development Disease Down-Regulation Drug Delivery Systems Endocannabinoids Epstein-Barr Virus Infections Event Experimental Designs Fibroblasts Foundations Frequencies Ganciclovir Gene Expression Gene Targeting Genes Genome Growth Herpes Simplex Infections Herpesviridae Herpesviridae Infections Human Human Herpesvirus 4 Human Herpesvirus 8 Immune Immune response Immune system Immunosuppression Immunosuppressive Agents In Vitro Individual Infection Infection Control Kidney Knock-out Knockout Mice Laboratory Animals Latent Virus Life Ligands Light Lung Lymphoid Lymphoid Cell Lymphoma Lytic Lytic Phase Malignant - descriptor Malignant Neoplasms Marijuana Marijuana Smoking Measures Mediating Messenger RNA Modeling Monitor Monkeys Mus Mutagenesis Open Reading Frames Organ Organ Transplantation Organism Pathogenesis Patients Pharmaceutical Preparations Physiological Population Predisposition Production Protein Kinase C Proteins Psychotropic Drugs Receptor Signaling Research Personnel Resistance Role Saimiriine Herpesvirus 2 Severities Signal Transduction Splenocyte System THC receptor Testing Tetrahydrocannabinol Time Transcriptional Regulation Transplant Recipients Viral Viral Genes Virus Virus Diseases Virus Replication Work base cannabinoid receptor cellular targeting cytokine cytotoxic design experience extracellular gammaherpesvirus human CREBBP protein in vivo infected B cell knockout animal latent infection lytic replication novel pathogen promoter reactivation from latency receptor research study response tissue culture tool viral DNA

项目摘要

Gamma or lymphotropic herpesviruses are characterized by their ability to cause a life-long latent infection in lymphoid cells. Epstein-Barr virus (EBV) and the Kaposi's Sarcoma Associated Herpesvirus (KSHV/HHV-8) are implicated as causative agents of malignant lymphomas in AIDS patients, in aging individuals, and organ transplant patients. The major psychoactive compound of marijuana delta-9 tetrahydrocannabinol (THC) has been shown to modulate lymphoid cell functions, therefore, we hypothesized that THC is likely to modulate gamma herpesvirus replication. The preliminary data show that THC inhibits lytic but not latent KSHV and EBV DMAreplication in B cell lines. THC also inhibits lytic replication of the murine gamma herpesvirus MHV 68 related to KSHV and EBV. THC inhibits these gamma herpesviruses in micromolar concentrations comparable with known antiviral drugs acyclovir and ganciclovir. However, concentration range of THC that inhibits these gamma herpesviruses is not cytotoxic and does not inhibit replication of herpes simplex type 1, an alpha herpesvirus, indicating selectivity. Based on these observations we hypothesize that THC inhibits gamma herpesviruses through a common mechanism that leads to block of lytic replication. However, THC is also immunosuppressive and may contribute to the development of a more serious gamma herpesvirus infection. The effects of THC on gamma herpesvirus infection will be tested by three aims. The experimental design relies primarily on the murine system that provides a tractable animal model. Aim 1 is planned to identify the gene(s) of MHV 68 inhibited by THC. Aim 2 is designed to evaluate the role of THC receptors (CB1 and CB2) in inhibition of MHV 68. Aim 3 is to examine the effects of THC and the role of CB receptors in vivo on virus replication and latency in mice. This study is significant because THC may modulate gamma herpesvirus latency and reactivation in people using marijuana. Approximately half of the US population will experience EBV infection that lasts for life and there are 4.8 million individuals who regularly use marijuana. We are not aware of any similar work performed in the past so this proposal represents the first study in this important area.

伽马或淋巴疱疹病毒的特征是它们引起终身潜在感染的能力淋巴样细胞。爱泼斯坦 - 巴尔病毒（EBV）和卡波西肉瘤相关的疱疹病毒（KSHV/HHV-8）与艾滋病患者，年龄个体和器官中的恶性淋巴瘤的病因有关移植患者。大麻Delta-9四氢大麻酚（THC）的主要心理活性化合物具有被证明可以调节淋巴样细胞功能，因此，我们假设THC可能调节伽马疱疹病毒复制。初步数据表明，THC抑制了裂解但不抑制潜在的KSHV，并且 B细胞系中的EBV Dmareplication。 THC还抑制鼠伽马疱疹病毒的裂解复制 MHV 68与KSHV和EBV有关。 THC以微摩尔浓度抑制这些γ疱疹病毒可与已知的抗病毒药物acyclovir和ganciclovir相当。但是，浓度范围是抑制这些伽马疱疹病毒不是细胞毒性的，并且不会抑制单纯疱疹1型的复制， α疱疹病毒，表明选择性。基于这些观察结果，我们假设THC抑制了伽马疱疹病毒通过通用机制，导致裂解复制的阻塞。但是，THC 也是免疫抑制的，可能有助于开发更严重的伽马病毒感染。 THC对γ疱疹病毒感染的影响将通过三个目标进行测试。这实验设计主要依赖于提供可拖动动物模型的鼠系统。目标1是计划鉴定THC抑制的MHV 68的基因。 AIM 2旨在评估THC的作用受体（CB1和CB2）在抑制MHV 68中。目标3是检查THC的作用和CB的作用在小鼠病毒复制和潜伏期的体内受体。这项研究很重要，因为THC可能调节使用大麻的人的伽马病毒潜伏期和重新激活。大约一半美国人口将经历EBV感染，持续一生，有480万个人定期使用大麻。我们不知道过去执行的任何类似的工作，所以此提案代表了这一重要领域的第一个研究。