Effect on CBD on Exosome release from CNS infected cells

CBD 对中枢神经系统感染细胞外泌体释放的影响

基本信息

批准号：
9884894
负责人：
Fatah Kashanchi
金额：
$ 21.1万
依托单位：
GEORGE MASON UNIVERSITY
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：
2020-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884894
关键词：
3-Dimensional Affect Anti-Retroviral Agents Autophagocytosis Binding Biological Assay Blood Brain Cannabidiol Cannabinoids Cell Culture Techniques Cell model Cells Cellular Stress Central Nervous System Viral Diseases ChIP-seq Collaborations Complex DNA Data Development Disease Down-Regulation Functional disorder Gene Expression Genetic Transcription Goals HIV HIV therapy HIV-1 HIV-associated neurocognitive disorder Human In Vitro Individual Infection Length Light Mediating Metabolism Microglia Morbidity - disease rate NF-kappa B Neurocognitive Neurons Pathogenesis Pathology Pathway interactions Predisposition Production RNA Reporting Role Serotonin Receptor 5-HT1A Sorting - Cell Movement T-Lymphocyte TLR3 gene Testing Tetrahydrocannabinol Therapeutic Therapeutic Effect Time Untranslated RNA Validation Viral Viral Proteins Virus Virus Replication antiretroviral therapy base cannabinoid treatment cytokine exosome extracellular vesicles follow-up genomic RNA induced pluripotent stem cell innovation macrophage nerve stem cell nervous system disorder neuroinflammation prevent promoter receptor binding repaired response restoration targeted treatment three dimensional cell culture vesicular release viral RNA

项目摘要

HIV-1 remains an incurable disease and as of 2017 over 30 million people were estimated to be living with HIV-1 with an average of 1.8 million new infections occurring annually. Up to 50% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND) despite effective combination anti-retroviral therapy (cART). HAND therefore represents a significant cause of morbidity in PWH. The inability of cART to prevent viral transcription and neurocognitive dysfunction confirms the need for adjunct therapies that target underlying mechanisms that contribute to HAND. In this context, mechanisms that may contribute to HAND include delivery of selective cargo in extracellular vesicles (EVs) released from HIV-infected macrophages/microglia. The long-term goal of this proposal is to mitigate virally-mediated pathogenesis within the CNS. The short term goals including elucidating the role of the cannabinoids in the inhibition of viral transcription and the reduction in the release of extracellular vesicles containing viral RNAs and proteins which cause CNS dysfunction. Our preliminary data suggests that the cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), may be effective in reducing HIV-1 transcription of both short, non-coding RNA such as trans-activating response (TAR) RNA and full- length genomic RNA, thereby resulting in a decreased production of infectious virus. Additional data indicates that the reduction in transcription results in a decreased incorporation of HIV-1 RNA into EVs released from infected cells, which has been previously shown to contribute to dysfunction in recipient cells including activation of the NF- kB pathway through TLR3 and increased susceptibility to infection. The data suggests this therapeutic effect is further amplified as treatment with cannabinoids results in a significant reduction in the number of EVs released from HIV-1 infected cells. We hypothesize that cannabinoid treatment may affect host cell pathways, including autophagy and the endosomal sorting complexes required for transport (ESCRT) pathways, to alter EV release which can potentially mitigate EV-related dysfunction during viral infection of the CNS. Our Aim include: 1) To define the mechanisms of cannabinoid-mediated decreased EV production and release in HIV-1 infected cells, and 2) Effect of CBD and THC on HIV-1 expression using 3D neurospheres. The overall positive impact of these two aims are to highlight the role of cannabinoids in EV release and dampening of the neuroinflammation.

HIV-1仍然是一种无法治愈的疾病，截至2017年，据估计有超过3000万人患有HIV-1 每年平均发生180万新感染。多达50％的艾滋病毒（PWH）患者患有尽管有效组合抗逆转录病毒疗法（CART），与HIV相关的神经认知障碍（手）。因此，手代表了PWH中发病率的重要原因。车无法防止病毒转录和神经认知功能障碍证实了针对靶向基础的辅助疗法的需求有助于手的机制。在这种情况下，可能有助于手的机制包括交付从HIV感染的巨噬细胞/小胶质细胞中释放出细胞外蔬菜（EV）的选择性货物。长期该建议的目标是减轻中枢神经系统内的虚拟介导的发病机理。短期目标包括阐明大麻素在抑制病毒转录中的作用以及释放的减少含有病毒RNA和蛋白质的细胞外蔬菜，引起CNS功能障碍。我们的初步数据表明大麻素，大麻二酚（CBD）和Δ9-四氢大麻酚（THC）可能在降低短而非编码RNA的HIV-1转录，例如反式激活反应（TAR）RNA和FULL- 长度基因组RNA，从而导致感染性病毒的产生降低。其他数据表明转录的降低导致将HIV-1 RNA纳入从感染的EV中减少以前已显示出可导致受体细胞功能障碍的细胞，包括激活NF- KB途径通过TLR3并增加了对感染的敏感性。数据表明这种治疗作用是随着大麻素治疗的进一步扩增导致释放的电动汽车数量显着减少来自HIV-1感染的细胞。我们假设大麻素治疗可能会影响宿主细胞途径，包括自噬和运输（ESCRT）途径所需的自噬和内体分类复合物，以更改EV释放在中枢神经系统的病毒感染期间，这可能会缓解与EV相关的功能障碍。我们的目标包括：1）定义大麻素介导的机制减少了HIV-1感染细胞中的EV产生和释放，以及 2）使用3D神经球对CBD和THC对HIV-1表达的影响。这两个的总体积极影响目的是强调大麻素在EV释放和神经炎症衰减中的作用。