Impact of THC on Extracellular Vesicle Signaling

鉴于最近美国大麻使用的增加，迫切需要更清楚地了解 大麻素对中枢和外周信号传导机制的影响。主要的精神活性成分 大麻，Δ9-四氢大麻酚（THC），已被证明直接作用于大麻素受体。这些 受体在中枢和外周细胞群中表达， 细胞外囊泡，包括脉络丛、神经元、神经胶质和脂肪细胞。其主要目标是 研究THC对脑和血液中细胞外囊泡信号传导的影响， 鉴定与THC使用相关的一组生物标志物。为了进一步验证生物标志物谱的选择性，RNA 将在存在另一种通常与大麻共同使用的药物尼古丁的情况下比较表达模式。 此后，我们将确定THC对细胞外囊泡密度和RNA货物的影响是否可以被抑制。 这归因于腹侧被盖区多巴胺能细胞的释放，腹侧被盖区是一个大脑区域， 加强和奖励滥用药物的属性。通过系统地检查细胞外 囊泡信号与THC暴露和有关的药物共同使用条件，这些研究试图揭示 对中枢和外周细胞外信号动力学的重要见解。此外，考虑到外围设备 miRNAs已被提议作为疾病状态的生物标志物，并且含有THC的大麻素经常被使用。 由患者，如癌症患者，研究结果可以进一步告知其他建议的相关性。 用于临床应用的生物标志物谱。最后，在此基础上，大麻素相关的细胞外 信号传导因子也可能导致识别潜在的药物依赖的细胞外机制 因此是治疗依赖性的治疗开发的潜在新靶点。

Given the recent increase in cannabis use in the US, there is an urgent need to more clearly understand the effects of cannabinoids on central and peripheral signaling mechanisms. The main psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), has been shown to act directly on the cannabinoid receptors. These receptors are expressed in both central and peripheral cellular populations that have been shown to secrete extracellular vesicles, including the choroid plexus, neurons, glia, and adipocytes. The main goals of this proposal are to investigate the effects of THC on extracellular vesicle signaling in the brain and blood and to identify a panel of biomarkers related to THC use. To further validate the selectivity of the biomarker profile, RNA expression patterns will be compared in the presence of another drug commonly co-used with cannabis, nicotine. Thereafter, we will determine whether THC's effects on extracellular vesicle density and RNA cargo can be attributed to release from dopaminergic cells in the ventral tegmental area, a brain region shown to mediate the reinforcing and rewarding properties of drugs of abuse. By systematically examining changes in extracellular vesicle signaling with THC exposure and relating to drug co-use conditions, these studies seek to reveal important insights into central and peripheral extracellular signaling dynamics. Further, given that peripheral miRNAs have been proposed as biomarkers of disease state, and THC-containing cannabinoids are often used by patients, such as individuals with cancer, findings may further inform on the relevance of other proposed biomarker profiles for clinical applications. Finally, with this foundation, cannabinoid-associated extracellular signaling factors may also lead to the identification of extracellular mechanisms underlying drug dependence and thus potential novel targets for therapeutic development to treat dependence.