Cannabinoid Epigenomic and miRNA mechanisms impact HIV/SIV disease progression

描述(申请人提供)：摘要9-THC是大麻中主要的精神活性大麻素。对其药理和主要的大麻素受体亚型(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确定。尤其重要的是9-THC对人类免疫缺陷病毒(HIV)感染者免疫功能的调节作用。我们的研究表明，慢性9-THC治疗可以减轻猴免疫缺陷病毒(SIV)感染非人类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，在体外试验中，9-THC降低了病毒复制。虽然其他人已经报道了大麻素抑制炎症和病毒复制的能力，并得到了我们正在进行的研究的证实，但其中涉及的机制尚不清楚。在这项应用的准备过程中获得的初步数据显示，在经THC治疗的SIV感染动物中，与免疫活性和抗炎特性(基于预测的靶点)降低有关的独特的miRNA图谱的表达增加。这些发现清楚地表明，调节大麻素保护作用的总体机制涉及新的表观基因组调节因子/机制，需要进行系统研究。这一建议的总体假设是，慢性9-THC治疗通过表观基因组(非编码RNA和DNA甲基化)机制减少促炎基因的表达和病毒复制。结果，慢性大麻素治疗延缓了感染SIV的非人类灵长类动物的疾病进展。这一假说将通过以下具体目标进行检验：1.证明慢性大麻素治疗可以减少感染SIV的恒河猴的组织炎症。2.确定大麻素抑制SIV感染猕猴炎症的表观基因组学(包括miRNAs和DNA甲基化)机制。3.研究大麻类物质减少病毒复制的直接和间接表观基因组学机制。拟议的研究将探索表观基因组学(miRNA和DNA甲基化)机制，涉及抗炎作用和抑制病毒复制，与延长THC治疗SIV感染动物的存活相关。公共卫生相关性：项目描述拟议的研究将探索表观基因组学(miRNA和DNA甲基化)机制，涉及抗炎效应和抑制病毒复制，与延长经THC治疗的SIV感染动物的存活有关。预期的结果将对制定有针对性的治疗干预措施以减缓艾滋病毒疾病进展的潜在发展产生深远影响。

DESCRIPTION (provided by applicant): Abstract 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 (CB2predominantly 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 application 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 pro-inflammatory 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. This hypothesis will be tested with the following specific aims: 1. Demonstrate that chronic cannabinoid treatment decreases tissue inflammation in SIV-infected rhesus macaques. 2. Identify the epigenomic (including miRNAs and DNA methylation) mechanisms of cannabinoid-induced suppression of inflammation in SIV-infected rhesus macaques. 3. Examine the direct and indirect epigenomic mechanisms by which cannabinoids decrease viral replication. The proposed studies will explore the epigenomic (miRNA and DNA methylation) mechanisms involved in the anti-inflammatory effects and suppression of viral replication associated with prolonged survival in chronic THC-treated SIV-infected animals. PUBLIC HEALTH RELEVANCE: Project Narrative The proposed studies will explore the epigenomic (miRNA and DNA methylation) mechanisms involved in the anti-inflammatory effects and suppression of viral replication associated with prolonged survival in chronic THC-treated SIV-infected animals. The expected results will have a profound impact on the potential development of targeted therapeutic interventions to ameliorate HIV disease progression.