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:
- 金额:$ 61.14万
- 依托单位:
- 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:
- 关键词:ABCG2 geneATP-Binding Cassette TransportersAddressAdhesionsAffectAgonistAnimal ModelAntiinflammatory EffectAseptic MeningitisAttenuatedBiological AssayBlood - brain barrier anatomyBrainCD44 geneCNR1 geneCNR2 geneCannabinoidsCannabisCellsCellular biologyChronicClinical ResearchCognitiveCommunitiesComplexDesire for foodDrug KineticsDwarfismEncephalitisEndocannabinoidsEndotheliumEnvironmentEnzymesEvaluationFunctional disorderGatekeepingGenesHIVHIV InfectionsHIV antiretroviralHIV therapyHumanImmuneImmunologic SurveillanceImmunologicsIndividualInfiltrationInflammationInflammatoryInflammatory ResponseInhalationInhalation Drug AdministrationKineticsMaintenanceMediatingMedical MarijuanaMicrofluidic MicrochipsMicrofluidicsMicrogliaModelingModernizationMolecularMolecular AnalysisMolecular WeightNeurocognitiveNeuronsOralOral AdministrationOutcomeOutputPPAR gammaPathologyPathway AnalysisPathway interactionsPersonsPhysical assessmentPhysiologicalPre-Clinical ModelPropertyProteinsProto-Oncogene Proteins c-aktRNAReceptor SignalingRegulationRoleRouteSignal TransductionStimulusSystemTechnologyTight JunctionsTissue EngineeringTracerTranscriptional RegulationVascular Cell Adhesion Molecule-1ViralViremiaVirusVirus Replicationantiretroviral therapybeta cateninblood-brain barrier functionblood-brain barrier permeabilizationbrain endothelial cellbrain tissuecannabinoid receptorcerebrovascularchronic paincytokineendogenous cannabinoid systemexperienceexperimental studyfluid flowhumanized mouseimmunoregulationin vivoindexinginnovationmacrophagemarijuana usemembermigrationmonocytemouse modelnervous system disorderneural networkneuroAIDSneuroinflammationneurovascular unitnoveloperationphytocannabinoidpre-clinicalprotein expressionreceptorresponsetoolvaping 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SUMARY /文摘
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Yuri Persidsky其他文献
Yuri Persidsky的其他文献
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{{ truncateString('Yuri Persidsky', 18)}}的其他基金
Injury of blood brain and alveolar-endothelial barriers caused by alcohol and electronic cigarettes via purinergic receptor signaling
酒精和电子烟通过嘌呤受体信号传导引起血脑和肺泡内皮屏障损伤
- 批准号:
10638221 - 财政年份:2023
- 资助金额:
$ 61.14万 - 项目类别:
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:
10536689 - 财政年份:2021
- 资助金额:
$ 61.14万 - 项目类别:
Inflammation associated with HIV infection: role of receptor cross-talk
与 HIV 感染相关的炎症:受体串扰的作用
- 批准号:
10434706 - 财政年份:2019
- 资助金额:
$ 61.14万 - 项目类别:
Inflammation associated with HIV infection: role of receptor cross-talk
与 HIV 感染相关的炎症:受体串扰的作用
- 批准号:
10663176 - 财政年份:2019
- 资助金额:
$ 61.14万 - 项目类别:
Inflammation associated with HIV infection: role of receptor cross-talk
与 HIV 感染相关的炎症:受体串扰的作用
- 批准号:
10016292 - 财政年份:2019
- 资助金额:
$ 61.14万 - 项目类别:
Inflammation associated with HIV infection: role of receptor cross-talk
与 HIV 感染相关的炎症:受体串扰的作用
- 批准号:
10190879 - 财政年份:2019
- 资助金额:
$ 61.14万 - 项目类别:
Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment
HIV感染并发糖尿病的血脑屏障损伤:预防认知障碍的机制和保护策略
- 批准号:
10400911 - 财政年份:2018
- 资助金额:
$ 61.14万 - 项目类别:
Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment
HIV感染并发糖尿病的血脑屏障损伤:预防认知障碍的机制和保护策略
- 批准号:
10160956 - 财政年份:2018
- 资助金额:
$ 61.14万 - 项目类别:
Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment
HIV感染并发糖尿病的血脑屏障损伤:预防认知障碍的机制和保护策略
- 批准号:
9918455 - 财政年份:2018
- 资助金额:
$ 61.14万 - 项目类别:
HIV-induced neuroinflammation associated with opiod abuse and tobacco smoke
艾滋病毒引起的与阿片类药物滥用和吸烟相关的神经炎症
- 批准号:
9153336 - 财政年份:2016
- 资助金额:
$ 61.14万 - 项目类别:
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