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叉,影响着全世界数百万人。抗逆转录病毒治疗(ART)
改善并延长了艾滋病毒感染者和艾滋病毒感染者的生命。然而,较轻微的慢性 HIV 相关
被称为轻度 HAND 或 HIV-NCI 的神经认知障碍持续存在。 HIV-NCI 影响 15-40% 的感染者和
因为它们会终生持续存在,随着年龄的增长而恶化,并影响药物的依从性,因此它们可以显着
降低生活质量并增加死亡风险。许多感染者患有阿片类药物使用障碍 (OUD),这是一种合并症
艾滋病毒感染者 (PWH) 可能会加剧 HIV-NCI。我们在第一个融资周期中的新发现表明,丁丙诺啡,
用于治疗 OUD 的成熟阿片类激动剂疗法也可能是 NCI 的一种疗法。丁丙诺啡
作为 mu 阿片受体 (MOR) 的部分激动剂和 kappa 阿片受体 (KOR) 的完全拮抗剂
根据一些研究,它可以改善患有或不患有 OUD 的人的神经心理学结果
慢性艾滋病毒感染。我们的研究表明,丁丙诺啡的这种有益活性可能是由于其
与外周血 CD14+CD16+ 单核细胞的相互作用,我们显示其表达 MOR 和 KOR,
优先感染艾滋病毒,并有选择性优势穿过血脑屏障(BBB)以应对
CCL2 体外。丁丙诺啡可以减少这种增加的迁移,部分原因是它能够限制
CCL2/CCR2 信号传导。我们在感染了 HIV-NCI 的 EcoHIV 小鼠中的新发现表明:
丁丙诺啡治疗可以逆转这些小鼠的 HIV-NCI,并与炎症减少相关
大脑中的单核细胞减少,艾滋病毒大脑负担减少,树突修剪减少,这是艾滋病毒的标志
介导的 NCI。我们假设丁丙诺啡可以减轻 HIV 神经发病机制并可以治疗 HIV-NCI
带和不带 OUD 的 PWH。我们还认为这是通过其对 Mu 和 Kappa 的活动来调节的
阿片受体。我们的研究还将确定丁丙诺啡发挥其机制的受体
行动并将促进源自丁丙诺啡的第二代疗法的开发
专门针对这些受体。在 Aim1 中,我们将描述丁丙诺啡的体外机制
介导的 CD14+CD16+ 单核细胞跨 BBB 迁移的抑制并表征 MOR 的作用
以及这些流程中的 KOR。在目标 2 中,我们将使用转基因小鼠来解决个体和组合问题
EcoHIV 驱动的 HIV-NCI 临床前模型中 MOR 和 KOR 在丁丙诺啡治疗中的作用以及
这些受体在 NCI 发展中对骨髓细胞的重要性。在目标 3 中,我们将描述
使用来自 PWH 的 PBMC,使用丁丙诺啡在成熟人单核细胞的 BBB 模型中进行轮回
并将其与感染者的认知功能联系起来。这些将为使用提供进一步的支持
丁丙诺啡在有或没有 OUD 的情况下作为艾滋病毒感染者 (HIV-NCI) 的治疗方法。这些研究将由
由艾滋病毒科学家、动物模型专家以及传染病、艾滋病毒和 OUD 组成的高度互动的小组
医学科学家和神经心理学家,都是公认的中枢神经系统疾病专家。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Joan Weinberger Berman其他文献
Joan Weinberger Berman的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
9407532 - 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:
9915978 - 财政年份:2017
- 资助金额:
$ 78.57万 - 项目类别:
相似海外基金
Pharmacy-led Transitions of Care Intervention to Address System-Level Barriers and Improve Medication Adherence in Socioeconomically Disadvantaged Populations
药房主导的护理干预转型,以解决系统层面的障碍并提高社会经济弱势群体的药物依从性
- 批准号:
10594350 - 财政年份:2023
- 资助金额:
$ 78.57万 - 项目类别:
Evaluating Centralizing Interventions to Address Low Adherence to Lung Cancer Screening Follow-up in Decentralized Settings
评估集中干预措施,以解决分散环境中肺癌筛查随访依从性低的问题
- 批准号:
10738120 - 财政年份:2023
- 资助金额:
$ 78.57万 - 项目类别:
Suubi-Mhealth: A mobile health intervention to address depression and improve ART adherence among Youth living with HIV (YLHIV) in Uganda
Suubi-Mhealth:一种移动健康干预措施,旨在解决乌干达艾滋病毒感染者 (YLHIV) 青少年的抑郁症问题并提高抗逆转录病毒疗法的依从性
- 批准号:
10526768 - 财政年份:2022
- 资助金额:
$ 78.57万 - 项目类别:
Suubi-Mhealth: A mobile health intervention to address depression and improve ART adherence among Youth living with HIV (YLHIV) in Uganda
Suubi-Mhealth:一种移动健康干预措施,旨在解决乌干达艾滋病毒感染者 (YLHIV) 青少年的抑郁症问题并提高抗逆转录病毒疗法的依从性
- 批准号:
10701072 - 财政年份:2022
- 资助金额:
$ 78.57万 - 项目类别:
A behavioral intervention for Black men who have sex with men and live with HIV to address intersectional stigma and improve antiretroviral therapy adherence
针对男男性行为且感染艾滋病毒的黑人男性进行行为干预,以解决交叉耻辱并提高抗逆转录病毒治疗的依从性
- 批准号:
10679092 - 财政年份:2021
- 资助金额:
$ 78.57万 - 项目类别:
A behavioral intervention for Black men who have sex with men and live with HIV to address intersectional stigma and improve antiretroviral therapy adherence
针对男男性行为且感染艾滋病毒的黑人男性进行行为干预,以解决交叉耻辱并提高抗逆转录病毒治疗的依从性
- 批准号:
10432133 - 财政年份:2021
- 资助金额:
$ 78.57万 - 项目类别:
A behavioral intervention for Black men who have sex with men and live with HIV to address intersectional stigma and improve antiretroviral therapy adherence
针对男男性行为且感染艾滋病毒的黑人男性进行行为干预,以解决交叉耻辱并提高抗逆转录病毒治疗的依从性
- 批准号:
10327065 - 财政年份:2021
- 资助金额:
$ 78.57万 - 项目类别:
Leveraging Technology to Address Access and Adherence to Conventional Hospital-Based Pulmonary Rehabilitation in Veterans with COPD
利用技术解决慢性阻塞性肺病退伍军人接受和坚持传统医院肺康复的问题
- 批准号:
10377366 - 财政年份:2019
- 资助金额:
$ 78.57万 - 项目类别:
Leveraging Technology to Address Access and Adherence to Conventional Hospital-Based Pulmonary Rehabilitation in Veterans with COPD
利用技术解决慢性阻塞性肺病退伍军人接受和坚持传统医院肺康复的问题
- 批准号:
10574496 - 财政年份:2019
- 资助金额:
$ 78.57万 - 项目类别:
Targeted interventions to address the multi-level effects of gender-based violence on PrEP uptake and adherence among adolescent girls and young women in Kenya
有针对性的干预措施,以解决性别暴力对肯尼亚少女和年轻妇女接受和坚持 PrEP 的多层面影响
- 批准号:
9403567 - 财政年份:2017
- 资助金额:
$ 78.57万 - 项目类别: