The role of cannabinoids in the regulation of the blood brain barrier in the context of NeuroHIV and anti-retroviral therapy

大麻素在 NeuroHIV 和抗逆转录病毒治疗背景下调节血脑屏障的作用

• 批准号: 10376762
• 负责人: Yuri Persidsky
• 金额: $ 61.14万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376762
• 关键词: ABCG2 gene; ATP-Binding Cassette Transporters; Address; Adhesions; Affect; Agonist; Animal Model; Antiinflammatory Effect; Aseptic Meningitis; Attenuated; Biological Assay; Blood - brain barrier anatomy; Brain; CD44 gene; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Cells; Cellular biology; Chronic; Clinical Research; Cognitive; Communities; Complex; Desire for food; Drug Kinetics; Dwarfism; Encephalitis; Endocannabinoids; Endothelium; Environment; Enzymes; Evaluation; Functional disorder; Gatekeeping; Genes; HIV; HIV Infections; HIV antiretroviral; HIV therapy; Human; Immune; Immunologic Surveillance; Immunologics; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Inhalation Drug Administration; Kinetics; Maintenance; Mediating; Medical Marijuana; Microfluidic Microchips; Microfluidics; Microglia; Modeling; Modernization; Molecular; Molecular Analysis; Molecular Weight; Neurocognitive; Neurons; Oral; Oral Administration; Outcome; Output; PPAR gamma; Pathology; Pathway Analysis; Pathway interactions; Persons; Physical assessment; Physiological; Pre-Clinical Model; Property; Proteins; Proto-Oncogene Proteins c-akt; RNA; Receptor Signaling; Regulation; Role; Route; Signal Transduction; Stimulus; System; Technology; Tight Junctions; Tissue Engineering; Tracer; Transcriptional Regulation; Vascular Cell Adhesion Molecule-1; Viral; Viremia; Virus; Virus Replication; antiretroviral therapy; beta catenin; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; brain tissue; cannabinoid receptor; cerebrovascular; chronic pain; cytokine; endogenous cannabinoid system; experience; experimental study; fluid flow; humanized mouse; immunoregulation; in vivo; indexing; innovation; macrophage; marijuana use; member; migration; monocyte; mouse model; nervous system disorder; neural network; neuroAIDS; neuroinflammation; neurovascular unit; novel; operation; phytocannabinoid; pre-clinical; protein expression; receptor; response; tool; vaping THC

PROJECT SUMARY/ABSTRACT Despite antiretroviral therapy (ART), neurocognitive complications continue to be highly prevalent in people living with HIV (PLWH). One explanation could be the constant compromise of the blood brain barrier (BBB) driven by chronic inflammatory responses. The introduction of medicinal marijuana into HIV treatment practice appear to be beneficial for several virus associated complications (ranging from chronic pain to appetite stimulation). Yet, the effects and mechanisms of cannabis on HIV associated chronic inflammation, the endocannabinoid system, immune modulation and neurologic disorders are minimally understood. As indicated in the RFA, preclinical models can provide a rigorous in-depth analysis of the molecular and cellular mechanisms at the intersection between phytocannabinoids, HIV and ART. To this end, we propose a comprehensive evaluation of the two most used cannabinoid compounds (THC, CBD) on BBB function, immune-endothelial interactions and neuroinflammation. We will utilize state of the art chip microfluidics models of the neurovascular unit (NVU) and animal models for HIV (w/ w/o ART). Previously, we discovered that the brain endothelium upregulate CB2 in HIV infected human brain tissue. We have also found that modulation of CB2 affects indices of HIV pathology (in-vivo) and regulates the BBB. Our preliminary studies identify the diverse effects that phytocannabinoids can have on the different properties of the BBB. Specifically, cannabinoids (THC, CBD) alone can enhance the physical barrier, partially reduce endothelial activation and augment efflux transporter activity. Although some of these effects may appear beneficial, the presence of HIV and ART changes how the function of the BBB is regulated by cannabinoid substances. For example, the augmented transporter activity by THC has important considerations for altering ART-CNS penetrability. Thus, we hypothesize that phytocannabinoids differentially modulates BBB function that are both beneficial and deleterious in NeuroHIV. In Aim 1, using our latest tissue-engineered microfluidic NVU model, we will perform analyses of the kinetic changes in BBB permeability, transporter status and immune-endothelial interaction. Then, in Aim 2, we will compare outcomes between widely used routes of cannabinoid administration (oral vs. inhaled) in vivo using two relevant models of HIV infection (‘humanized’ mice and a model of aseptic meningitis/encephalitis). Experiments will evaluate changes in the BBB in the context of ART and cannabinoid exposure. Finally, we propose to identify novel crosstalk mechanisms that bridge cannabinoid receptor signaling to signals that control BBB maintenance (Aim 3). It’s clear that cannabinoids exert unknown cell specific effects that contribute to the tumultuous interpretation of how these compounds impact NeuroHIV. Using innovative preclinical tools, our studies will contribute significantly towards understanding the consequences of cannabinoid use on the BBB in the modern era of NeuroHIV.

项目总结/摘要 尽管有抗逆转录病毒治疗（ART），但神经认知并发症仍然在人群中高度流行。 艾滋病毒携带者（PLWH）。一种解释可能是血脑屏障（BBB）的持续损害 由慢性炎症反应驱动。将药用大麻引入艾滋病毒治疗实践 似乎对几种病毒相关的并发症（从慢性疼痛到食欲）有益 刺激）。然而，大麻对HIV相关慢性炎症的作用和机制， 对内源性大麻素系统、免疫调节和神经系统疾病的了解最少。示 在RFA中，临床前模型可以提供分子和细胞的严格深入分析， 在植物大麻素，艾滋病毒和艺术之间的交叉机制。为此，我们提出了一个 两种最常用的大麻素化合物（THC、CBD）对BBB功能的综合评价， 免疫-内皮相互作用和神经炎症。我们将利用最先进的芯片微流体技术 神经血管单位（NVU）模型和HIV动物模型（w/ w/o ART）。此前，我们发现 在HIV感染的人脑组织中，脑内皮细胞上调了CB 2。我们还发现 CB 2的调节影响HIV病理学指标（体内）并调节BBB。我们的初步研究 确定植物大麻素对血脑屏障不同特性的不同影响。具体地说， 单独的大麻素（THC，CBD）可以增强物理屏障，部分减少内皮激活， 增加外排转运蛋白活性。虽然其中一些效果可能是有益的，但艾滋病毒的存在 ART改变了大麻素物质对血脑屏障功能的调节方式。比如说 THC增强的转运蛋白活性对于改变ART-CNS穿透性具有重要的考虑。因此，在本发明中， 我们假设植物大麻素对血脑屏障功能的调节是不同的， 对神经HIV病毒有害在目标1中，使用我们最新的组织工程微流体NVU模型，我们将 分析血脑屏障通透性、转运蛋白状态和免疫内皮细胞功能的动态变化。 互动然后，在目标2中，我们将比较广泛使用的大麻素途径之间的结果 使用两种相关的HIV感染模型（“人源化”小鼠和“人源化”小鼠）， 无菌性脑膜炎/脑炎模型）。实验将评估ART背景下BBB的变化 和大麻素暴露最后，我们建议确定新的串扰机制，桥梁大麻素 受体信号传导到控制BBB维持的信号（Aim 3）。很明显大麻素发挥了未知的 细胞特异性效应，有助于对这些化合物如何影响NeuroHIV的混乱解释。 使用创新的临床前工具，我们的研究将大大有助于了解 在NeuroHIV的现代时代大麻素使用对BBB的后果。