Impact of μ-opioid receptor (MOR) splice variant interactions with the chemokine receptor CCR5 in the context of morphine and HIV-1 entry inhibitor therapy
在吗啡和 HIV-1 进入抑制剂治疗背景下,μ-阿片受体 (MOR) 剪接变异体与趋化因子受体 CCR5 相互作用的影响
基本信息
- 批准号:9064917
- 负责人:
- 金额:$ 18.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgonistAntiviral AgentsApplications GrantsAreaAstrocytesBindingBiological AssayBiological ProcessBrainCCR5 geneCell Surface ReceptorsCell fusionCellsCo-ImmunoprecipitationsDevelopmentDiseaseDisease ProgressionEpitopesFishesGenetic PolymorphismGoalsGrantHIVHIV Entry InhibitorsHIV encephalitisHeterodimerizationHumanIndividualInflammationInvestigationKnowledgeMass Spectrum AnalysisMediatingMediationMethodsMicrogliaMorphineN-terminalNeuraxisNeurocognitive DeficitNeurogliaNeurologicOpiatesOpioidOpioid ReceptorPathogenesisPharmaceutical PreparationsPlasmidsProcessProtein IsoformsRNA SplicingRegulationReportingRoleSignal TransductionTransfectionTreatment outcomeVariantViralbasecell typechemokinechemokine receptorclinically relevantdesigndrug abuserinhibitor/antagonistneuroAIDSopioid abuseopioid useoverexpressionpublic health relevancereceptor
项目摘要
DESCRIPTION (provided by applicant): Growing evidence suggests that opioid abuse exacerbates neuroAIDS and these effects are mainly mediated through the μ-opioid receptor (MOR). There is also evidence to suggest that MOR-1 may have a direct role in HIV type-1 (HIV-1) replication and pathogenesis. MOR is not a single entity, but instead exists as multiple isoforms that differs in function. Despite significant fundamental differences, most studies examining MOR have focused on the canonical MOR-1, and this is particularly true in studies of opioid drug-HIV interactions. Although MOR-1- HIV-1interactions have been studied extensively, the role of MOR splice variant regulation by HIV and, conversely, MOR variant regulation of HIV cellular binding and entry is an unexplored area. Therefore, given that MOR-1 is thought to interact with HIV co-receptors such as CCR5 via heterodimerization and/or downstream signaling, the goal of this grant is to address the variation of MOR in relation to CCR5 mediation of HIV-associated processes in the CNS in the context of morphine and the HIV-1 entry inhibitor maraviroc. Preliminary studies found that: (i) MOR-1 may not be the predominate form of MOR on all CNS cell types, (ii) the N-terminal variant MOR-1K differs functionally in cellular signaling compared to MOR-1 (iii) although both astrocytes and microglia harbors multiple MOR variants, astrocytes harbors the most (iv) MOR-CCR5 interaction occurs in both microglia and astrocytes, although more so in astrocytes and (iv) morphine the predominant agonist of MOR was able to abolish the antiviral effect of the CCR5-mediated viral entry inhibitor maraviroc in a MOR-dependent manner in both astrocytes and microglia. The present proposal is designed to 1. (i) identify the MOR splice variants that interact with the chemokine and HIV (co-) receptor CCR5 in glia (astroglia and microglia) and (ii) determine how these interactions affect viral entry in opioid using individuals in the context of the clinically relevant viral entry inhibitor maraviroc which targets CCR5-mediated entry. The findings from this project could further define the mechanisms in the progression of HIV-related complications in opioid abusers by targeting specific MOR variants and whether a particular cell type is modulating the vulnerability to these complications in the CNS. These findings may also extend to further develop HIV entry inhibitors targeting this interaction.
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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NAZIRA EL-HAGE其他文献
NAZIRA EL-HAGE的其他文献
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{{ truncateString('NAZIRA EL-HAGE', 18)}}的其他基金
Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV
HIV背景下星形胶质细胞自噬在大脑稳态和阿片类药物诱导的适应不良行为和成瘾中的功能
- 批准号:
10619748 - 财政年份:2023
- 资助金额:
$ 18.13万 - 项目类别:
Develop and evaluate efficacy of nanoformulated siBeclin1 delivered intranasally to eliminate HIV in brain
开发并评估鼻内递送的纳米制剂 siBeclin1 消除大脑中 HIV 的功效
- 批准号:
9893032 - 财政年份:2019
- 资助金额:
$ 18.13万 - 项目类别:
Impact of μ-opioid receptor (MOR) splice variant interactions with the chemokine receptor CCR5 in the context of morphine and HIV-1 entry inhibitor therapy
在吗啡和 HIV-1 进入抑制剂治疗背景下,μ-阿片受体 (MOR) 剪接变异体与趋化因子受体 CCR5 相互作用的影响
- 批准号:
9308938 - 财政年份:2016
- 资助金额:
$ 18.13万 - 项目类别:
Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse
自噬在小胶质细胞诱导的药物滥用中的神经艾滋病中的作用
- 批准号:
8823758 - 财政年份:2014
- 资助金额:
$ 18.13万 - 项目类别:
Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse
自噬在小胶质细胞诱导的药物滥用中的神经艾滋病中的作用
- 批准号:
8919084 - 财政年份:2014
- 资助金额:
$ 18.13万 - 项目类别:
Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse
自噬在小胶质细胞诱导的药物滥用中的神经艾滋病中的作用
- 批准号:
9036365 - 财政年份:2014
- 资助金额:
$ 18.13万 - 项目类别:
Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse
自噬在小胶质细胞诱导的药物滥用中的神经艾滋病中的作用
- 批准号:
9264742 - 财政年份:2014
- 资助金额:
$ 18.13万 - 项目类别:
Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse
自噬在小胶质细胞诱导的药物滥用中的神经艾滋病中的作用
- 批准号:
8584593 - 财政年份:2013
- 资助金额:
$ 18.13万 - 项目类别:
Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse
自噬在小胶质细胞诱导的药物滥用中的神经艾滋病中的作用
- 批准号:
8701265 - 财政年份:2013
- 资助金额:
$ 18.13万 - 项目类别:
Oxidative damage and proteasome activity: Role of opioid in HIV-HCV infection
氧化损伤和蛋白酶体活性:阿片类药物在 HIV-HCV 感染中的作用
- 批准号:
7777398 - 财政年份:2009
- 资助金额:
$ 18.13万 - 项目类别:
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