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

基本信息

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
项目类别：
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

项目摘要

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/摘要尽管进行了抗逆转录病毒治疗（ART），神经认知并发症在人群中仍然非常普遍艾滋病毒感染者（PLWH）的一种解释可能是血脑屏障（BBB）的不断受损。由慢性炎症反应驱动，将药用大麻引入艾滋病毒治疗实践。似乎对多种病毒相关并发症（从慢性疼痛到食欲不振）有益然而，大麻对艾滋病毒相关慢性炎症的影响和机制。正如所示，人们对内源性大麻素系统、免疫调节和神经系统疾病了解甚少。在 RFA 中，临床前模型可以提供对分子和细胞的严格深入分析为此，我们提出了一种植物大麻素、HIV 和 ART 之间的交叉机制。综合评价两种最常用的大麻素化合物（THC、CBD）对BBB功能的影响，我们将利用最先进的芯片微流体技术。此前，我们发现了神经血管单元 (NVU) 模型和 HIV 动物模型（不含 ART）。我们还发现，在 HIV 感染的人脑组织中，脑内皮细胞会上调 CB2。 CB2 的调节影响 HIV 病理学指标（体内）并调节 BBB。确定植物大麻素对 BBB 不同特性的不同影响。大麻素（THC、CBD）单独可以增强物理屏障，部分减少内皮激活和虽然其中一些效应可能看起来是有益的，但艾滋病毒的存在。 ART 改变了大麻素物质调节 BBB 功能的方式。 THC 增强的转运蛋白活性对于改变 ART-CNS 渗透性具有重要的考虑因素。我们认为植物大麻素可以差异调节 BBB 功能，这两者都是有益的在目标 1 中，使用我们最新的组织工程微流体 NVU 模型，我们将对 BBB 通透性、转运蛋白状态和免疫内皮细胞的动力学变化进行分析然后，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”小鼠和无菌性脑膜炎/脑炎模型）实验将评估 ART 背景下 BBB 的变化。最后，我们建议确定桥接大麻素的新型串扰机制。受体信号转导控制 BBB 维持的信号（目标 3）很明显，大麻素的作用未知。细胞特异性效应导致了对这些效应如何影响 NeuroHIV 的混乱解释。使用创新的临床前工具，我们的研究将极大地有助于理解在现代 NeuroHIV 时代，大麻素的使用对血脑屏障的影响。