Effect of buprenorphine on monocytes in the context of neuroAids and opioid abuse
神经辅助药物和阿片类药物滥用中丁丙诺啡对单核细胞的影响
基本信息
- 批准号:10618101
- 负责人:
- 金额:$ 78.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-15 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAddressAdherenceAffectAgeAgonistAnimal ModelBiologyBloodBlood - brain barrier anatomyBrainBuprenorphineCCL2 geneCD14 geneCellsCentral Nervous System DiseasesChronicCommunicable DiseasesDNADataDementiaDevelopmentDiseaseFCGR3B geneFundingGenerationsHIVHIV InfectionsHIV therapyHumanImpaired cognitionIn VitroIndividualInflammationInflammatoryLaboratoriesLeadLifeLinkMalignant NeoplasmsMediatingMediator of activation proteinMethadoneModelingMusMyeloid CellsNeurocognitive DeficitNeuropathogenesisNeuropsychologyNeurovirologyNew York CityOpioidOpioid AntagonistOpioid ReceptorOpioid replacement therapyOutcomePeripheralPeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPhysiciansPre-Clinical ModelProcessPropertyQuality of lifeResearchRoleSafetyScientistSeveritiesSignal TransductionSpecialistSynapsesTherapeuticTimeViralViral Load resultWithdrawaladdictionantagonistantiretroviral therapybuprenorphine treatmentchemokinecognitive functioncognitive testingcomorbidityexperienceimprovedin vivoinnovationkappa opioid receptorsmacrophagemigrationmonocytemortality riskmouse modelmu opioid receptorsneuroAIDSneuroinflammationneurotoxicnovelopioid abuseopioid agonist therapyopioid epidemicopioid use disorderoverdose riskperipheral bloodprescription opioidpreventreceptorresponseside effect
项目摘要
The HIV and opioid epidemics intersect, impacting millions of people worldwide. Antiretroviral therapy (ART)
has improved and extended the lives of people with HIV, PWH. However, milder chronic HIV associated
neurocognitive impairments known as mild HAND or HIV-NCI persist. HIV-NCI affect 15-40% of PWH and
because they persist for life, worsen with age, and affect adherence to medications, they can significantly
reduce quality of life and increase mortality risk. Many PWH have opioid use disorder, OUD, a comorbidity in
PWH that can exacerbate HIV-NCI. Our novel findings in the first funding cycle demonstrate that buprenorphine,
a well-established opioid agonist therapy used to treat OUD, may also be a therapy for NCI. Buprenorphine
acts as a partial agonist to the mu opioid receptor (MOR) and full antagonist to the kappa opioid receptor (KOR)
and according to some studies, it may improve neuropsychological outcomes in people with OUD with or without
chronic HIV infection. Our studies suggest that this beneficial activity of buprenorphine may due to its
interactions with peripheral blood CD14+CD16+ monocytes, which we showed express MOR and KOR, are
preferentially infected with HIV, and have a selective advantage to cross the blood brain barrier (BBB) in response to
CCL2 in vitro. This increased transmigration is reduced by buprenorphine, in part by its ability to limit
CCL2/CCR2 signaling. Our novel findings in EcoHIV infected mice with HIV-NCI demonstrate that
buprenorphine treatment can reverse HIV-NCI in these mice in correlation with a decrease in inflammatory
monocytes in their brains, reduction in HIV brain burden, and a reduction in dendritic pruning, a marker of HIV
mediated NCI. We hypothesize that buprenorphine mitigates HIV neuropathogenesis and can treat HIV-NCI in
PWH with and without OUD. We also propose that this is mediated through its activity on the Mu and Kappa
opioid receptors. Our studies will also identify receptor(s) by which buprenorphine is exerting its mechanism of
action and will enable the development of second-generation therapies derived from buprenorphine that
specifically target these receptor(s). In Aim1, we will characterize in vitro mechanisms of buprenorphine
mediated inhibition of CD14+CD16+ monocyte transmigration across the BBB and characterize the role of MOR
and KOR in these processes. In Aim 2, we will use genetically modified mice to address individual and combined
roles of MOR and KOR in buprenorphine therapy in the preclinical model of EcoHIV driven HIV-NCI and the
importance of these receptors specifically on myeloid cells in NCI development. In Aim 3, we will characterize
transmigration across a BBB model of mature human monocytes using PBMC from PWH on buprenorphine
and correlate this with the PWH's cognitive functions. These will provide further support for use of
buprenorphine as a therapy for HIV-NCI in PWH with and without OUD. The studies will be performed by a
highly interactive group of HIV scientists, animal model specialists, and infectious diseases, HIV, and OUD
physician scientists, and a neuropscychologist, all recognized experts in CNS disease.
艾滋病毒和阿片类药物流行病相互交织,影响着全世界数百万人。抗逆转录病毒治疗(ART)
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joan Weinberger Berman其他文献
Joan Weinberger Berman的其他文献
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{{ truncateString('Joan Weinberger Berman', 18)}}的其他基金
The impact of methamphetamine on CXCL12 mediated HIV neuropathogenesis
甲基苯丙胺对 CXCL12 介导的 HIV 神经发病机制的影响
- 批准号:
10547875 - 财政年份:2022
- 资助金额:
$ 78.57万 - 项目类别:
Inflammation, BBB disruption, and Reward Function in the Pathogenesis of Depression among PWH
感染者抑郁症发病机制中的炎症、血脑屏障破坏和奖赏功能
- 批准号:
10535898 - 财政年份:2022
- 资助金额:
$ 78.57万 - 项目类别:
The impact of methamphetamine on CXCL12 mediated HIV neuropathogenesis
甲基苯丙胺对 CXCL12 介导的 HIV 神经发病机制的影响
- 批准号:
10666675 - 财政年份:2022
- 资助金额:
$ 78.57万 - 项目类别:
Inflammation, BBB disruption, and Reward Function in the Pathogenesis of Depression among PWH
感染者抑郁症发病机制中的炎症、血脑屏障破坏和奖赏功能
- 批准号:
10707230 - 财政年份:2022
- 资助金额:
$ 78.57万 - 项目类别:
Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
- 批准号:
10383747 - 财政年份:2019
- 资助金额:
$ 78.57万 - 项目类别:
Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
- 批准号:
9767913 - 财政年份:2019
- 资助金额:
$ 78.57万 - 项目类别:
Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
- 批准号:
9919529 - 财政年份:2019
- 资助金额:
$ 78.57万 - 项目类别:
Mechanisms of opioid- mediated HIV neuropathogenesis
阿片类药物介导的 HIV 神经发病机制
- 批准号:
10612386 - 财政年份:2019
- 资助金额:
$ 78.57万 - 项目类别:
Monocyte CNS HIV entry & neurodegeneration: Translational studies in the CART era
单核细胞 CNS HIV 进入
- 批准号:
9915978 - 财政年份:2017
- 资助金额:
$ 78.57万 - 项目类别:
Monocyte CNS HIV entry & neurodegeneration: Translational studies in the CART era
单核细胞 CNS HIV 进入
- 批准号:
9407532 - 财政年份:2017
- 资助金额:
$ 78.57万 - 项目类别:
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