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: 9064917
• 负责人: NAZIRA EL-HAGE
• 金额: $ 18.13万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9064917
• 关键词: Address; Affect; Agonist; Antiviral Agents; Applications Grants; Area; Astrocytes; Binding; Biological Assay; Biological Process; Brain; CCR5 gene; Cell Surface Receptors; Cell fusion; Cells; Co-Immunoprecipitations; Development; Disease; Disease Progression; Epitopes; Fishes; Genetic Polymorphism; Goals; Grant; HIV; HIV Entry Inhibitors; HIV encephalitis; Heterodimerization; Human; Individual; Inflammation; Investigation; Knowledge; Mass Spectrum Analysis; Mediating; Mediation; Methods; Microglia; Morphine; N-terminal; Neuraxis; Neurocognitive Deficit; Neuroglia; Neurologic; Opiates; Opioid; Opioid Receptor; Pathogenesis; Pharmaceutical Preparations; Plasmids; Process; Protein Isoforms; RNA Splicing; Regulation; Reporting; Role; Signal Transduction; Transfection; Treatment outcome; Variant; Viral; base; cell type; chemokine; chemokine receptor; clinically relevant; design; drug abuser; inhibitor/antagonist; neuroAIDS; opioid abuse; opioid use; overexpression; public health relevance; receptor

 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.

 描述（由适用提供）：越来越多的证据表明，阿片类药物滥用加剧了神经辅助，这些作用主要是通过μ阿片受体（MOR）介导的。也有证据表明，MOR-1在HIV类型1（HIV-1）复制和发病机理中可能具有直接作用。 MOR不是一个单一的实体，而是作为多种同工型存在的，在功能方面有所不同。尽管存在很大的基本差异，但大多数研究MOR的研究都集中在规范的MOR-1上，而在阿片类药物-HIV相互作用的研究中尤其如此。尽管已经对MOR-1-HIV-1间隔术进行了广泛的研究，但HIV和相反的MOR剪接变体调节的作用是HIV细胞结合和进入的MOR变体调节是一个意外的区域。因此，鉴于MOR-1被认为是通过异二聚化和/或下游信号与HIV共受体相互作用（例如CCR5），因此该授予的目的是解决MOR与MOR与HIV相关过程中CNS中CNS中CNS中的CCR5介导的变化，而HIV-1进入了Morphine和Hiv-1进入Inibyitor 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,尽管在星形胶质细胞和（iv）吗啡中更是如此，MOR的主要激动剂能够在星形胶质细胞和小胶质细胞中以MOR依赖性的方式废除CCR5介导的病毒入口抑制剂Maraviroc的抗病毒作用。 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.该项目的发现可以进一步定义阿片类药物滥用者中HIV相关并发症进展的机制，通过靶向特定的MOR变体以及特定细胞类型是否正在调节CNS中这些并发症的脆弱性。这些发现也可能扩展到进一步发展针对这种相互作用的HIV进入抑制剂。