CANNABINOID EPIGENOMIC AND MIRNA MECHAMISMS IMPACT HIV/SIV DISEASE PROGRESSION

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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（CB 1和CB 2）及其定位（CB 2主要位于B淋巴细胞和自然杀伤细胞上）的深入了解已导致多系统生物医学效应的鉴定。特别重要的是9-THC调节人免疫缺陷病毒（HIV）感染个体的免疫功能的潜力。我们的研究表明，慢性9-THC治疗减弱猴免疫缺陷病毒（SIV）感染的非人灵长类动物的病毒载量和组织炎症，显著降低SIV感染的发病率和死亡率。此外，9-THC在体外测定中降低病毒复制。虽然大麻素抑制炎症和病毒复制的能力已经被其他人报道，并被我们正在进行的研究证实，但所涉及的机制尚不清楚。在为该项目做准备时获得的初步数据显示，在THC处理的SIV感染动物的CD 4 + T淋巴细胞、肠粘膜和脑中，与免疫激活和抗炎特性（基于预测的靶点）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总体机制涉及需要系统研究的新表观基因组调控因子/机制。该建议的总体假设是，慢性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，慢性大麻素治疗延缓了SIV感染的非人灵长类动物的疾病进展。7只动物（2只THC+ SIV+、2只THC-/SIV+、2只THC+/SIV-、1只仅溶剂对照）已分配至第1年的研究，该项目目前正在进行中。

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.