Impact of THC on Extracellular Vesicle Signaling

THC 对细胞外囊泡信号传导的影响

基本信息

批准号：
10398914
负责人：
CHRISTIE D FOWLER
金额：
$ 36.93万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398914
关键词：
Abstinence Acute Adipocytes Alleles Biological Markers Blood Brain Brain region CD81 gene CNR1 gene CNR2 gene Cannabinoids Cannabis Cerebrospinal Fluid Choroid Choroid Plexus Epithelium Chronic Cre driver Data Dependence Development Disease Dopamine Dopaminergic Cell Drug Addiction Drug usage Epithelial Cells Female Foundations Genetic Transcription Goals Human Hypermethylation In Vitro Individual Lead Malignant Neoplasms Mediating MicroRNAs Microscopy Mus NCAM1 gene Neural Cell Adhesion Molecules Neuroglia Neurons Nicotine Patients Pattern Peripheral Pharmaceutical Preparations Plasma Population Property RNA Rattus Research Resistance Rewards Signal Transduction Structure of choroid plexus Surface THC exposure Tetrahydrocannabinol Therapeutic Tissues Tobacco use Transgenic Mice Validation Variant Ventral Tegmental Area Virus base biomarker panel cannabinoid receptor cell type clinical application density dopaminergic neuron drug of abuse extracellular extracellular vesicles genome wide association study in vivo innovation insight integration site male marijuana use marijuana user new therapeutic target nicotine exposure novel promoter receptor receptor expression relating to nervous system response sex specific biomarkers therapeutic development transcriptome sequencing uptake vesicular release

项目摘要

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.

鉴于美国最近使用大麻的使用，迫切需要更清楚地了解大麻素对中央和外围信号传导机制的影响。主要的心理活性组成部分大麻Δ9-四氢大麻醇（THC）已被证明直接作用于大麻素受体。这些受体在中央和周围细胞种群中均表现为秘密细胞外蔬菜，包括脉络丛，神经元，神经胶质和脂肪细胞。主要目标建议是研究THC对大脑和血液中细胞外囊泡信号传导的影响确定与使用THC相关的生物标志物小组。为了进一步验证生物标志物曲线的选择性，RNA 在存在另一种通常与大麻尼古丁共同使用的药物存在下，将比较表达模式。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是归因于腹侧换段区域中多巴胺能细胞的释放，这是一个显示介导的大脑区域加强和奖励滥用药物的特性。通过系统地检查细胞外的变化囊泡信号传导与THC暴露并与药物共用条件有关，这些研究试图揭示对中央和周围细胞外信号动力学的重要见解。此外，考虑到外围已提出miRNA作为疾病状态的生物标志物，经常使用含THC的大麻素患者（例如癌症患者）可能会进一步告知其他提议的相关性用于临床应用的生物标志物谱。最后，有了这个基础，大麻素相关的细胞外信号传导因子也可能导致鉴定药物依赖的细胞外机制因此，治疗依赖性的治疗发育的潜在新靶标。