Elucidating the role of Ephrin-b1 in Interferon Beta (IFN-beta) mediated neuroprotection in HIV associated neurocognitive disorder (HAND)

阐明 Ephrin-b1 在干扰素 Beta (IFN-beta) 介导的 HIV 相关神经认知障碍 (HAND) 神经保护中的作用

• 批准号: 10548011
• 负责人: Jeffrey Koury
• 金额: $ 3.9万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548011
• 关键词: Ablation; Address; Animals; Anti-Inflammatory Agents; Astrocytes; Behavioral; Biological Assay; Brain Pathology; CCR5 gene; CXCR4 gene; Cell surface; Cells; Data; Diagnosis; Disease; Eph Family Receptors; EphB2 Receptor; Ephrin B Receptor; Ephrin-B1; Ephrins; Excision; Family; Gene Expression; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interferon-beta; Interferons; Lead; Ligands; Light; Mediating; Mediator of activation protein; Messenger RNA; Microglia; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Neurocognitive; Neurodegenerative Disorders; Neuronal Injury; Neurons; Pathology; Patients; Persons; Phenotype; Phosphorylation; Production; Proteins; RNA; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recombinant Interferon Beta; Recombinant Proteins; Research; Role; SIV; STAT3 gene; Signal Transduction; Speech; Stains; Structure; Surface; Synapses; Synaptic plasticity; Synaptophysin; Synaptosomes; System; Therapeutic; Transgenic Mice; Transgenic Organisms; Up-Regulation; Viral; Viral Proteins; Work; axon guidance; cytokine; gephyrin; glial activation; immune function; in vivo; in vivo Model; induced pluripotent stem cell; inflammatory marker; insight; knock-down; motor disorder; mouse model; nano-string; neuroAIDS; neuroinflammation; neuron development; neuroprotection; neurotoxicity; novel; prevent; protein expression; recruit; response; synaptic pruning

Project Abstract 37 million people worldwide are diagnosed with Human Immunodeficiency Virus (HIV). Of these 37 million, an estimated 15-55% of people living with HIV develop HIV-associated neurocognitive disorder (HAND). Previous work in ours and other labs identifies a transient increase of interferon beta (IFNβ), and antiviral type 1 interferon, preceding any behavioral or neuropathological signs in the HIVgp120 transgenic mouse and SIV models, suggesting a neuroprotective role for IFNβ in early HIV infection. We have previously shown that exogenous intranasal exposure of HIVgp120tg animals with IFNβ is sufficient to confer neuroprotection. Preliminary data from our lab describes the ability of HIVgp120 viral protein and IFNβ to regulate an important cell surface transmembrane ligand, ephrin-B1, in the CNS. Neuronal ephrin-B1 has been well studied and implicated in neuronal development, recruitment of NMDA receptors and synaptic plasticity mainly through its signaling with EphB receptors. However, ephrin-B1’s functional role in HIV, particularly microglial specific ephrin-B1, has not been well characterized at all. Our preliminary data identifies a statistically significant upregulation in EphB2 mRNA (one of the main receptors of ephrin-B1) in the cortex of HIV+ Patients with brain pathology. In addition, we describe significant inverse correlations between ephrin-B1 mRNA in the cortex of HIV+ Patients with both neurocognitive domain scores and inhibitory neuronal gene expression. In a transgenic NeuroHIV mouse in vivo model, we show in the cortex and hippocampus that the presence of gp120 upregulates ephrin-B1 protein expression in a cell-specific manner, including microglia. Treatment with IFNβ marginally reduces ephrin-B1 expression but significantly reduces ephrin-B1 off the surface of microglia. We believe that enhanced signaling between EphB2 and ephrin-B1 in the CNS of HIV+ Patients may lead to enhanced inflammatory response as well as unwanted synaptic pruning, and ablation of microglial ephrin-B1 will, in part, mitigate inflammation and synaptic pruning. This proposal seeks to identify the functional consequences of regulating microglial ephrin-B1 on microglial state and neuronal health in the context of HIV.

项目摘要 全世界有3700万人被诊断出患有人类免疫缺陷病毒（HIV）。在这3700万，一个 估计有15-55％的HIV患者发展了与HIV相关的神经认知障碍（HAND）。以前的 在我们和其他实验室中的工作可以确定干扰素β（IFNβ）和抗病毒1型干扰素的短暂增加， 在HIVGP120转基因小鼠和SIV模型中的任何行为或神经病理学迹象之前， 提示IFNβ在早期HIV感染中起神经保护作用。我们以前已经表明了外源 IFNβ的HIVGP120TG动物的鼻内暴露足以赋予神经保护作用。初步数据 从我们的实验室中描述了HIVGP120病毒蛋白和IFNβ调节重要细胞表面的能力 CNS中的跨膜配体Ephrin-B1。神经元ephrin-b1已经进行了很好的研究，并实施了 神经元发展，NMDA接收器的募集和突触可塑性主要通过其信号传导 EPHB受体。但是，ephrin-b1在艾滋病毒中的功能作用，尤其是小胶质特异性ephrin-b1，尚未 完全是特征的。 我们的初步数据确定了EPHB2 mRNA中统计学上显着的上调（主要受体之一） 在患有脑病理学的HIV+患者的皮质中以ephrin-b1）的形象。此外，我们描述了重要的逆 均神经认知结构域评分的HIV+患者皮质中的Ephrin-B1 mRNA之间的相关性 和抑制性神经元基因表达。在体内模型的转基因神经hiv小鼠中，我们在皮质中显示 海马，GP120的存在会以细胞特异性方式上调ephrin-b1蛋白表达 包括小胶质细胞。 IFNβ的治疗略微降低了Ephrin-B1的表达，但显着降低 小胶质细胞表面的ephrin-b1。我们认为，在 HIV+患者中枢神经系统可能导致炎症反应增强以及不必要的突触修剪，并且 小胶质细胞蛋白-B1的消融将部分减轻注射和突触修剪。该提议试图 确定对小胶质细胞蛋白-B1对小胶质细胞状态和神经元健康的功能后果 在艾滋病毒的背景下。