CANNABINOID EPIGENOMIC AND MIRNA MECHAMISMS IMPACT HIV/SIV DISEASE PROGRESSION

大麻素表观基因组和 miRNA 机制影响 HIV/SIV 疾病进展

• 批准号: 8358169
• 负责人: Mahesh Mohan
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358169
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; B-Lymphocytes; Brain; CD4 Positive T Lymphocytes; Cannabinoids; Chronic; DNA Methylation; Data; Disease Progression; Functional RNA; Funding; Gene Expression; Grant; HIV; Individual; Inflammation; Intestinal Mucosa; Investigation; Marijuana; Mediating; MicroRNAs; Morbidity - disease rate; National Center for Research Resources; Natural Killer Cells; Pharmacology; Preparation; Primates; Principal Investigator; Property; Reporting; Research; Research Infrastructure; Resources; SIV; Source; Tissues; United States National Institutes of Health; Viral; Viral Load result; Virus Diseases; base; cannabinoid receptor; cost; epigenomics; immune activation; immune function; in vitro Assay; mortality; nonhuman primate; novel; protective effect

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 9-THC is the major psychoactive cannabinoid in marijuana. Advanced understanding of its pharmacology and the major cannabinoid receptor subtypes (CB1 and CB2) as well as their localization (CB2 predominantly on B lymphocytes and natural killer cells) has resulted in identification of multisystemic biomedical effects. Particularly important is the potential of 9-THC modulation of immune function in human immunodeficiency virus (HIV) infected individuals. Our studies indicate that chronic 9-THC treatment attenuates viral load and tissue inflammation in simian immunodeficiency virus (SIV) infected non-human primates, significantly decreasing morbidity and mortality from SIV infection. In addition, 9-THC decreased viral replication in an in vitro assay. While the ability of cannabinoids to suppress inflammation and viral replication has been reported by others and confirmed by our ongoing studies, the mechanisms involved are not known. Preliminary data obtained in preparation for this project revealed increased expression of a distinct miRNA profile associated with decreased immune activation and anti-inflammatory properties (based on predicted targets) in CD4+ T lymphocytes, intestinal mucosa, and brain of THC-treated SIV infected animals. These findings clearly suggest that the overall mechanisms mediating the protective effects of cannabinoids involve novel epigenomic regulatory factors/mechanisms in need of systematic investigation. The overall hypothesis of this proposal is that chronic 9-THC treatment decreases proinflammatory gene expression and viral replication through epigenomic (non-coding RNAs and DNA methylation) mechanisms. As a result, chronic cannabinoid treatment delays disease progression in SIV-infected non-human primates. Seven animals have been assigned (2 THC+ SIV+, 2 THC-/SIV+, 2 THC+/SIV-, 1 Vehicle only control) to the study for year 1 and the project is currently in progress.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 9-THC 是大麻中主要的精神活性大麻素。对其药理学和主要大麻素受体亚型（CB1 和 CB2）及其定位（CB2 主要在 B 淋巴细胞和自然杀伤细胞上）的深入了解，导致了多系统生物医学效应的鉴定。特别重要的是 9-THC 对人类免疫缺陷病毒 (HIV) 感染者免疫功能的调节潜力。我们的研究表明，长期 9-THC 治疗可减轻猿猴免疫缺陷病毒 (SIV) 感染的非人类灵长类动物的病毒载量和组织炎症，显着降低 SIV 感染的发病率和死亡率。此外，在体外试验中，9-THC 还降低了病毒复制。虽然大麻素抑制炎症和病毒复制的能力已被其他人报道并得到我们正在进行的研究的证实，但所涉及的机制尚不清楚。为该项目做准备而获得的初步数据显示，在 THC 治疗的 SIV 感染动物的 CD4+ T 淋巴细胞、肠粘膜和大脑中，与免疫激活和抗炎特性（基于预测目标）降低相关的独特 miRNA 谱的表达增加。这些发现清楚地表明，介导大麻素保护作用的整体机制涉及需要系统研究的新型表观基因组调节因素/机制。该提案的总体假设是，长期 9-THC 治疗通过表观基因组（非编码 RNA 和 DNA 甲基化）机制降低促炎基因表达和病毒复制。因此，长期大麻素治疗可延缓 SIV 感染的非人类灵长类动物的疾病进展。已将 7 只动物（2 只 THC+ SIV+、2 只 THC-/SIV+、2 只 THC+/SIV-、1 只车辆对照）分配到第一年的研究中，该项目目前正在进行中。